Pyranone compounds useful to treat retroviral infections

ABSTRACT

The present invention relates to compounds of formulae (I) and (II) which are pyran-2-ones, 5,6-dihydro-pyran-2-ones, 4-hydroxy-benzopyran-2-ones, 4-hydroxy-cycloalkyl b!pyran-2-ones, and derivatives thereof, useful for inhibiting a retrovirus in a mammalian cell infected with said retrovirus, wherein R 10  and R 20  taken together are formulae (III) and (IV). ##STR1##

CROSS-REFERENCE

This application is a 371 of PCT/US95/05219 filed May 4, 1995, which isa Continuation of U.S. Ser. No. 08/349,361 filed Dec. 2, 1994 (nowabandoned), which is a Continuation of U.S. Ser. No. 08/238,817 filedMay 6, 1994 (Abandoned).

The present invention relates to compounds useful for inhibiting aretrovirus in a human cell infected with said retrovirus. Moreparticularly, the present invention provides pyran-2-ones,5,6-dihydropyran-2-ones, 4-hydroxy-benzopyran-2-ones,4-hydroxy-cycloalkyl b!pyran-2-ones, and derivatives thereof asHIV-proteinase inhibitors.

BACKGROUND OF THE INVENTION

During the past decade, acquired immunodeficiency syndrome (AIDS) hasprogressed from having the status of a medical curiosity afflicting onlya small number of individuals to a problem of major proportions, bothmedically and economically. John Saunders and Richard Storer, "NewDevelopments in RT Inhibitors," DN&P 5(3), April 1992, pages 153-169.WHO figures reveal that more than 360,000 cases of AIDS have beenreported worldwide, including nearly 175,000 cases in the U.S.A. Ofthese, approximately 100,000 worldwide (50,000 in the U.S.A.) werereported in the preceding 12-month period. In the U.S.A., the number ofseropositive individuals is thought to be approximately two million, andestimates suggest that 5-10 million people worldwide may beseropositive. Saunders and Storer, page 153.

Since the first description of the malady in the early part of thisdecade, acquired immunodeficiency disease syndrome (AIDS) and itsdevastating consequences have been subjects of continuous and intensecoverage in both the lay and scientific press. Indeed, an edition ofScientific American was entirely devoted to AIDS (Scientific American289, #4 (1988)), and the literature on the disease and the virus isalready so vast as to defy thorough citation.

On Mar. 20, 1987, the FDA approved the use of the compound, zidovudine(AZT), to treat AIDS patients with a recent initial episode ofpneumocystis carinii pneumonia, AIDS patients with conditions other thanpneumocystis carinii pneumonia or patients infected with the virus withan absolute CD4 lymphocyte count of less than 200/mm³ in the peripheralblood. AZT is a known inhibitor of viral reverse transcriptase, anenzyme necessary for human immunodeficiency virus replication. U.S. Pat.No. 4,724,232 claims a method of treating humans having acquiredimmunodeficiency syndrome utilizing 3'-azido-3'-deoxy-thymidine(azidothymidine, AZT).

Following the discovery of the anti-HIV activity of AZT, much effort hasbeen focused on a wide variety of other dideoxynucleoside analogues inthe search for superior agents. In the case of the 2'.3'-dideoxy series,ddC and ddI have shown potent activity against HIV in vitro and havebeen evaluated in clinical trials. Saunders and Storer, page 160. Thecompound ddC is currently being developed by Hoffman-La Roche Co. as apotential anti-AIDS drug. Its limiting toxicity in humans is peripheralneuropathy which is reversible at low doses. Raymond R. Schinazi, Jan R.Mead and Paul M. Feorino, "Insights Into HIV Chemotherapy," AIDSResearch and Human Retroviruses, Vol. 8, Number 6, 1992, pages 963-990.It has been approved by the FDA for AIDS therapy in combination withAZT. The compound ddI has also been evaluated in clinical trials. Itslimiting toxicities are peripheral neuropathy and pancreatitis. It hasalso been shown to stimulate hepatic glycolysis leading to irreversibleliver damage. Schinazi, Mead and Feorino, page 966. It has recently beenapproved by the FDA for the treatment of HIV-1 infections in adults andpediatric patients who are intolerant to or whose health hassignificantly deteriorated while on AZT treatment. Schinazi, Mead andFeorino, page 966.

Among these approved drugs, AZT is currently the only drug that has beenshown to decrease the mortality and frequency of opportunisticinfections associated with AIDS. Schinazi, Mead and Feorino, page 963.

Human immunodeficiency virus (HIV) has long been recognized as thecausative agent in AIDS, although a minority opinion to the contrary hasbeen expressed (e.g., P. Duesberg, Proc. Natl. Acad. Sci., USA,86:755-764 (1989)). Sequence analysis of the complete genomes fromseveral infective and non-infective HIV-isolates has shed considerablelight on the make-up of the virus and the types of molecules that areessential for its replication and maturation to an infective species.The HIV protease is essential for the processing of the viral gag andgag-pol polypeptides into mature virion proteins. L. Ratner, et al.,Nature, 313:277-284 (1985); L. H. Pearl and W. R. Taylor, Nature,329:351 (1987). HIV exhibits the same gag/pol/env organization seen inother retroviruses. L. Ratner, et al., above; S. Wain-Hobson, et al.,Cell, 40:9-17 (1985); R. Sanchez-Pescador, et al., Science, 227:484-492(1985); and M. A. Muesing, et al., Nature, 313:450-458 (1985).

Reverse transcriptase (RT) is an enzyme unique to retroviruses thatcatalyzes the conversion of viral RNA into double stranded DNA. Blockageat any point during the transcription process, by AZT or any otheraberrant deoxynucleoside triphosphate incapable of elongation, shouldhave dramatic consequences relative to viral replication. Much work onthe RT target is in progress based, in large measure, upon the fact thatnucleosides like AZT are easily delivered to cells. However, theinefficiency of phosphorylation steps to the triphosphate, and the lackof specificity and consequent toxicity, constitute major drawbacks touse of AZT and similar nucleosides having a blocked, or missing,3'hydroxyl group.

The T4 cell receptor for HIV, the so-called CD4 molecule, has also beentargeted as an intervention point in AIDS therapy. R. A. Fisher, et al.,Nature, 331:76-78 (1988); R. E. Hussey, et al., Nature, 331:78-81(1988); and K. C. Deen, et al., Nature, 331:82-84 (1988). The exteriorportion of this transmembrane protein, a molecule of 371 amino acids(sCD4) has been expressed in Chinese hamster ovary (CHO) cells andGenentech (D. H. Smith, et al., Science, 238:1704-1707 (1987)) has had aproduct in clinical trials since the fall of 1987. CD4 has been shown tohave a narrow spectrum of activity against wild-type virus and so farhas failed to control HIV infection in humans. Schinazi, Mead andFeorino, page 963. The idea behind CD4 based therapy is that themolecules can neutralize HIV by interfering with viral attachment to T4,and other cells which express CD4 on their surfaces. A variant on thistheme is to attach cell toxins to CD4 for specific binding and deliveryto infected cells which display glycoprotein gp-120 on their surfaces.M. A. Till, et al., Science, 242:1166-1168 (1988); and V. K. Chaudhary,et al., Nature, 335:369-372 (1988).

Another therapeutic target in AIDS involves inhibition of the viralprotease (or proteinase) that is essential for processing HIV-fusionpolypeptide precursors. In HIV and several other retroviruses, theproteolytic maturation of the gag and gag/pol fusion polypeptides (aprocess indispensable for generation of infective viral particles) hasbeen shown to be mediated by a protease that is, itself, encoded by thepol region of the viral genome. Y. Yoshinaka, et al., Proc. Natl. Acad.Sci. USA, 82:1618-1622 (1985); Y. Yoshinaka, et al., J. Virol.,55:870-873 (1985); Y. Yoshinaka, et al., J. Virol., 57:826-832 (1986);and K. von der Helm, Proc. Natl. Acad. Sci., USA, 74:911-915 (1977).Inhibition of the protease has been shown to inhibit the processing ofthe HIV p55 in mammalian cell and HIV replication in T lymphocytes. T.J. McQuade, et al., Science, 247:454 (1990).

The protease (or proteinase), consisting of only 99 amino acids, isamong the smallest enzymes known, and its demonstrated homology toaspartyl proteases such as pepsin and renin (L. H. Pearl and W. R.Taylor, Nature, 329:351-354 (1987); and I. Katoh, et al., Nature,329:654-656 (1987)), led to inferences regarding the three-dimensionalstructure and mechanism of the enzyme (L. H. Pearl and W. R. Taylor,above) that have since been borne out experimentally. Active HIVprotease has been expressed in bacteria (see, e.g., P. L. Darke, et al.,J. Biol. Chem., 264:2307-2312 (1989)) and chemically synthesized (J.Schneider and S. B. Kent, Cell, 54:363-368 (1988); and R. F. Nutt, etal., Proc. Natl. Acad. Sci., USA, 85:7129-7133 (1988)). Site directedmutagenesis (P. L. Darke, et al., above); and N. E. Kohl, et al., Proc.Natl. Acad. Sci., USA, 85:4686-4690 (1988)) and pepstatin inhibition (P.L. Darke, et al., J. Biol. Chem., 264:2307-2312 (1989); S. Seelmeier, etal., Proc. Natl. Acad. Sci., USA, 85:6612-6616 (1988); C.-Z. Giam and I.Borsos, J. Biol. Chem., 263:14617-14720 (1988); and J. Hansen, et al.,EMBO J., 7:1785-1791 (1988)) have provided evidence for HIV protease'smechanistic function as an aspartyl protease. A study has demonstratedthat the protease cleaves at the sites expected in peptides modeledafter the regions actually cleaved by the enzyme in the gag and polprecursor proteins during viral maturation. P. L. Darke, et al.,Biochem. Biophys. Res. Communs., 156:297-303 (1988). X-raycrystallographic analysis of the HIV-protease (M. A. Navia, et al.,Nature, 337:615-620 (1989)) and a related retroviral enzyme from Roussarcoma virus (M. Miller, et al., Nature, 337:576-579 (1989)) reveal anactive site in the protease dimer that is identical to that seen inother aspartyl proteases, thus supporting the supposition (L. H. Pearland W. R. Taylor, above) that the HIV enzyme is active as a dimer. Seealso Joseph A. Martin, "Recent Advances in the Design of HIV ProteinaseInhibitors," Antiviral Research, 17 (1992) 265-278.

To date, the scientific search for a fully effective and safe means ofinhibiting retroviruses in a human hosting such a virus, and therebyeffectively treating diseases caused by such a virus, such as acquiredimmunodeficiency syndrome (AIDS), continues.

INFORMATION DISCLOSURE

JO 3227-923-A (Sawai Seiyaku KK) discloses the use of4-hydroxy-coumarins as therapeutic agents for HIV-infected patients;however, unsubstituted 4-hydroxy-coumarin is the only compoundspecifically disclosed for this use.

WO 91/04663 (Univ. of Calif. at Oakland) discloses6-amino-1,2-benzopyrones which are useful for treating viral diseases.

WO 91/12804 (Kabi Pharmaceutical), published 5 Sep. 1991, discloses theuse ofN-phenyl-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamidealso known as Linomide®, for the treatment of retrovirus infections.

International Publication No. WO 89/07939, published 8 Sep. 1989,discloses specific coumarin compounds which are reverse transcriptaseinhibitors.

U.S. Pat. Nos. 3,489,774 and 3,493,586 disclose3-(beta-aryl-beta-(arylthio) (or aryl seleno) propionyl-coumarin andpyrone products useful as parasiticides.

Biochemical and Biophysical Research Communications, Vol. 188, No. 2,1992, pages 631-637, discloses chromones bearing hydroxyl substituentsand a phenolic group at the 2-position (flavones) as having anti-HIV-1proteinase activity.

Antimicrobial Patent Fast-Alert, Week Ending 4 Sep. 1992, disclosegamma-pyrones, gamma-pyridones and gamma-thio-pyrones as antiviralagents.

International Publication Nos. WO 92/04326, 92/04327 and 92/04328, allpublished 19 Mar. 1992, disclose antiviral heterocyclic derivatives,such as quinolinones and benzopyranones, as replication inhibitors fortreating herpes simples 1 and 2, cytomegalovius and Epstein-Barr virus.

C.A. Selects: Antitumor Agents, Issue 19, 1992, page 25, No. 117:90147q(PCT International Application WO 92 06,687) discloses the preparationof 5-iodo-5-amino-1,2-benzopyrones and analogs as cytostatic andantiviral agents.

Nowhere do these references teach or suggest the use of4-hydroxy-α-pyrones as HIV protease inhibitors or as having antiviralactivity.

Phytochemistry, 31(3):953-956 (1992), discloses compounds, such as4-hydroxy-α-(4-methoxyphenyl)-6- 2-(4-methoxyphenyl)ethenyl!-2-oxo-,methyl ester, (E)-(-)-2H-pyran-3-acetic acid.

Tetrahedron, 48(9):1695-1706 (1992), (see also Tetrahedron Lett.,30(23):3109-12 (1989)), discloses compounds, such as 3-1-(4-chlorophenyl)-3-(4-nitrophenyl)-2-propenyl!-4-hydroxy-6-methyl-2H-pyran-2-one;3-3-(4-chlorophenyl)-1-(4-nitrophenyl)-2-propenyl!-4-hydroxy-6-methyl-2H-pyran-2-one;4-hydroxy-3-3-(4-methoxyphenyl)-1-(4-nitrophenyl)-2-propenyl!-6-methyl-2H-pyran-2-one;and 4-hydroxy-3-1-(4-methoxyphenyl)-3-(4-nitrophenyl)-2-propenyl!-6-methyl-2H-pyran-2-one.

Tennen Yuki Kagobutsu Toronkai Koen Yoshishu, 30:17-24 (1988), disclosescompounds, such as 4-hydroxy-β-(4-methoxyphenyl)-6-2-(4-methoxyphenyl)ethenyl!-2-oxo-, methyl ester,(E)-(-)-2H-pyran-3-propanoic acid.

Chem. Absts. 53:15072f discloses compounds, such asα-1,3-dihydroxy-2-butenylidene-β-ethyl-, δ-lactone, hydrocinnamic acid.

Chem. Absts. 53:15072c discloses compounds, such asα-1,3-dihydroxy-2-butenylidene-β-isopropyl-, δ-lactone, hydrocinnamicacid.

Arch. Pharm. (Weinheim, Ger.), 316(12):988-94 (1983), disclosescompounds, such as 3-1-(4-chlorophenyl)-3-oxobutyl!-4-hydroxy-6-methyl-2H-pyran-2-one; and 3-1-(4-chlorophenyl)propyl!-4-hydroxy-6-methyl-2H-pyran-2-one.

Chem. Ber., 110(3):1047-57 (1977), discloses compounds, such as6-(3,4-dimethoxyphenyl)-3-2-(3,4-dimethoxy-phenyl)-1-(4-methoxy-2-oxo-2H-pyran-6-yl)ethyl!-4-hydroxy-2H-pyran-2-one;and 3-2-(3,4-dimethoxyphenyl)-1-(4-methoxy-2-oxo-2H-pyran-6-yl)ethyl-4-hydroxy-6-2-(4-methoxyphenyl)ethyl!-2H-pyran-2-one.

J. Heterocycl. Chem., 23(2):413-16 (1986), discloses compounds, such as3-(4-chlorophenyl)-1-piperidinylmethyl!-4-hydroxy-6-methyl-2H-pyran-2-one.

The following published PCT applications disclose peptides useful asretroviral protease inhibitors: International Publication No. WO91/06561, published 16 May 1991; and International Publication No. WO92/17490, published 15 Oct. 1992.

The following references disclose pyrone compounds which are believed tobe representative of those known in the art:

EP-443449 (German language) discloses3-hexyl-5,6-dihydro-6-pentyl-2H-pyran-2-one and3-ethyl-6-hexadecyl-5,6-dihydro-4-hydroxy-2H-pyran-2-one. Pestic. Sci.,27(1):45-63 (1989), discloses5,6-dihydro-4-hydroxy-6-methyl-6-(1-methyl-1-propenyl)-3-(1-oxobutyl)-2H-pyran-2-one;and6-cyclopropyl-5,6-dihydro-4-hydroxy-6-methyl-3-(1-oxobutyl)-2H-pyran-2-one.Acta. Chem. Scand., 43(2):193-95 (1989), discloses4-(acetyloxy)-5,6-dihydro-3,6-dimethyl-2H-pyran-2-one. J. Org. Chem.,54(14):3383-9 (1989), discloses5,6-dihydro-4-hydroxy-3,6,6-trimethyl-2H-pyran-2-one. J. Org. Chem.,53(6):1218-21 (1988); and Tetrahedron Lett., 34(2):277-80 (1993),discloses 3-hexyldihydro-6-undecyl-2H-pyran-2,4 (3H)-dione, (6R)-. J.Chem. Soc. Perkins Trans., 1(6):1157-9 (1985), disclosesdihydro-3-methyl-6-nonyl-6-(tetrahydro-2H-pyran-2-yl)oxy!methyl!-2H-pyran-2,4 (3H)-dione. J. Chem.Ecol., 9(6):703-14 (1983), discloses5,6-dihydro-4-hydroxy-3,6-dimethyl-2H-pyran-2-one. J. Org. Chem.,48(7):1123-5 (1983), discloses6-(2-chloro-1-methylethenyl-5,6-dihydro-4-hydroxy-3-methyl-2H-pyran-2-one,(Z)-(±)-. Acta. Chem. Scand., 43(2):193-95 (1989); and TetrahedronLett., 21(6):551-4 (1980), discloses5,6-dihydro-4-hydroxy-3,6-dimethyl-2H-pyran-2-one. Helv. Chem. Acta,59(7):2393-2401 (1976), discloses 4-(3,6-dihydro-4-hydroxy-5-methyl-6-oxo-2H-pyran-2-yl)methyl!-2,6-piperidinedione.Acta. Chem. Scand., 30(7):613-18 (1976); and Tetrahedron Lett.,22:1903-4 (1976), discloses5,6-dihydro-4-hydroxy-3-methyl-6-(1-methyl-1-propenyl)-2H-pyran-2-one,(E)-. 3,3'- (4-nitrophenyl)methylene!bis5,6-dihydro-4-hydroxy-6-methyl-2H-pyran-2-one; and3,3'-(phenylmethylene)bis 5,6-dihydro-4-hydroxy-6-methyl-2H-pyran-2-oneare disclosed in Synth. Commun., 20(18):2827-2836, 1990.

WO 93/07868, published 29 Apr. 1993, discloses new nitroso-benzopyrone,-benzamide and -isoquinolinone derivatives as adenosinedi-phospho:ribose transferase inhibitors for treating viral infectionsand cancer.

WO 93/07128, published 15 Apr. 1993, relates to substituted cycliccarbonyls and derivatives thereof useful as retroviral proteaseinhibitors.

J. Indian Chem. Soc., 69:397-398 (July 1992), discloses thatcoumarin-4-acetic acids were screen for their anticancer and anti-AIDSactivities and were found to be inactive.

The Journal of Antibiotics, 46(7):1126 (July 1993), disclosesgermicidin, which is 6-(2-butyl)-3-ethyl-4-hydroxy-2-pyrone, to be anautoregulative germination inhibitor of Streptomyces viridochromogenesNRRL B-1551.

Derwent Abstracts, 93-168920/21 of EP 543201 discloses the use ofcoumarin derivatives, such as 1-(N-morpholyl)-6-(4-hydroxybenzoic acidethyl ester) hexane, for the treatment of viral infections, such asinfluenza or acute rhinitis.

J. Org. Chem., 48(22):3945-7 (1983); and Chem. Pharm. Bull.,29(10):2762-8 (1981); disclose compounds such as4-hydroxy-6-(3-pyridinyl)-2H-pyran-2-one.

J. Labelled Compd. Radiopharm., 28(10):1143-8 (1990), disclosescompounds such as 4-hydroxy-6-methyl-2H-pyran-2-one.

J. Am. Chem. Soc., 113(25):9585-95 (1991), discloses compounds such as3-(3-phenyl-2-propen-1-yl)-6-methyl-4-hydroxy-2H-pyran-2-one.

CA 54:14239d and CA 53:4272c disclose compounds such asα-(α,γ-dihydroxycinnamylidene)-, δ-lactone hydrocinnamic acid.

CA 53:15072f discloses compounds such asα-1,3-dihydroxy-2-butenylidene-β-ethyl-, δ-lactone hydrocinnamic acid.

Synth. Commun., 20(18):2827-36 (1990), discloses compounds such as 3,3'-(4-nitrophenyl)methylene!bis5,6-dihydro-4-hydroxy-6-methyl-2H-pyran-2-one, and3,3'-(phenylmethylene)bis 5,6-dihydro-4-hydroxy-6-methyl-2H-pyran-2-one.

J. Org. Chem., 54(14):3383-9 (1989), discloses compounds such as5,6-dihydro-4-hydroxy-3,6,6-trimethyl-2H-pyran-2-one.

Derwent Abstract, 92-166863/20, of EP 553248 discloses new optionallysubstituted 5-iodo-6-amino-1,2-benzopyrone derivatives, which areadenosine di:phospho-ribose inhibitors, for treatment and prevention ofviruses and tumors associated with AIDS.

Synthesis of Heterocycles. XV. 4-Hydroxy-2-pyronocyclenes. E. Ziegler,H. Junek, and E. Nolken, Monatsh., 89:678-82 (1958) (CA 53:12283-4)discloses compounds such as the following:4-hydroxy-3-benzyl-5,6-octamethylene-2-pyrone;4-hydroxy-3-benzyl-5,6-pentamethylene-2-pyrone;4-hydroxy-3-benzyl-5,6-heptamethylene-2-pyrone;4-hydroxy-3-benzyl-5,6-hexamethylene-2-pyrone; and4-hydroxy-3-benzyl-5,6-tridecamethylene-2-pyrone.

R. Effenberberger, T. Ziegler, K.-H. Schonwalder, T. Kesmarszky, B.Bauer, Chem. Ber 119:3394-3404 (1986), discloses pyrone intermediates,such as those of formula J-1 (wherein n is 4; refer to Chart J below).

Monatsh. Chem., 119(6-7):727-37 (1988) (CA 110(13):114430k) disclosesthe compounds 8H-acenaphtho 1,2-b!pyran-8-one,10-hydroxy-9-(phenylmethyl)-; and indeno 2,1-b!pyran-3(5H)-one,1-hydroxy-2-(phenylmethyl)-.

CA 54:14239b discloses the compound 3-benzyl-4-hydroxy-2-oxoindeno-1,2-b!pyran.

Monatsh. Chem., 113(4):475-84 (1982) discloses compounds such as6,7-dihydro-4-hydroxy-6-(3-methylphenyl)-7-phenyl-3-(phenylmethyl)-pyrano2,3-c!pyrrole-2,5-dione;and 6,7-dihydro-4-hydroxy-6,7-diphenyl-3-(phenylmethyl)-pyrano2,3-c!pyrrole-2,5-dione.

Monatsh. Chem. 90:594-9 (1959) (CA 54:14238g,h) discloses compounds suchas 5H-benzocycloheptene-8-acrylic acid,α-benzyl-6,7-dihydro-β,-9-dihydroxy-,δ-lactone; and3-benzyl-5,6,7,8-tetrahydro-4-hydroxy-8-isopropyl-5-methyl-coumarin.

Bull. Soc. Chim. Fr. 5:1719-23 (1069) (Fr) (CA 71(21):101655p) disclosesthe compound 3-benzyl-5,6,7,8-tetrahydro-4-hydroxy-coumarin.

WO 8804652 (equivalent AU 8810440 (Jap.)) discloses the compound3-(4-chloro-2-nitrobenzoyl)-5,6,7,8-tetrahydro-4-hydroxy-2H-1-benzopyran-2-one.

Monatsh. 92:246-53 (1961) (Gr) (CA 55:27296d) discloses the compound3-(3,5-dimethylsalicyl)-5,6,7,8-tetrahydro-4-hydroxy-coumarin.

CA 94(9):65472r discloses 5,6,7,8-hexahydro-3-phenyl-2-H-cyclooctab!pyran-2-one; and 6,7,8,9-tetrahydro-4-hydroxy-3-phenyl-cycloheptab!pyran-2(5H)-one.

J. Org. Chem. 28(11):3112-14 (1963) (CA 59:15185e) discloses thecompound hexanedioic acid, 2-hydroxy(2-hydroxy-1-cyclopenten-1-yl)methylene!-, δ-lactone.

Antimicrobial Patent Fast-Alert, Week Ending 30 Apr. 1993, disclosescyclic ureas and analogues useful as retroviral protease inhibitors.

Many 4-hydroxy-coumarin type compounds are known. For example, thesereferences--CA 54:577e,g,h (1960); U.S. Pat. No. 2,872,457 (CA 53:12305e(1959)); CA 51:14826f,h (1957); U.S. Pat. No. 2,723,276 (CA 52:5480g,h(1958)); CA 51:14827a,b (1957); CA 51:16453a (1957); CA 54:5699d (1960);CA 54:16450f (1960); CA 53:22454a (1959); and CA 53:20046a--disclosecompounds such as the following: 4-hydroxy-3-(1-phenylbutyl)-coumarin;4-hydroxy-3-(1-phenylpentyl)-coumarin;3-(cyclohexylphenylmethyl)-4-hydroxycoumarin;4-hydroxy-3-(2-methyl-1-phenylpropyl)-coumarin;4-hydroxy-3-(2-phenylpropyl) coumarin;4-hydroxy-3-(1,3-diphenylpropyl)-coumarin;4-hydroxy-3-(1-(4-methylphenyl)-butyl)-coumarin;4-hydroxy-3-(1-(1-naphthyl)-propyl)-coumarin;4-hydroxy-7-methyl-3-(1-phenylpropyl)-coumarin;7-chloro-4-hydroxy-3-(1-phenylpropyl)-coumarin; 4-hydroxy-3-1-(4-methoxyphenyl)propyl!-coumarin;3-(α-ethyl-p-fluorobenzyl)-4-hydroxy-coumarin;3-(α-ethyl-p-methoxybenzyl)-4-hydroxy-coumarin; and3-(1-phenyl-propenyl)-4-hydroxy-coumarin.

To the best of our knowledge, from our review, these references do notdisclose the use of these compounds as HIV protease inhibitors. They aredisclosed as being useful as: rodenticides, lowering the prothrombinlevel of the blood, blood anticoagulants, and pesticides.

Additional 4-hydroxy-coumarin compounds with similar uses have beendisclosed in the following references:

Indian J. Chem., Sect. B, 25B: 1167-70 (1986) (CA 107(17):154201f) andCA 93(23):220546t discloses the compound4-Hydroxy-3-(1-phenyl-2-propenyl)-coumarin.

CA 96(19):157432x; CA 90(1):1707f; CA 84(9):55338f; CA 79(13):74969a;and CA 71(15):69677j disclose the compound 4-hydroxy-3-1-(1,2,3,4-tetrahydro)naphthyl!-coumarin; CA 54:579e discloses thecompound 4-hydroxy-3- 1-indanyl!-coumarin; CA 63:14743c discloses thecompound 4-hydroxy-3-(1-naphthylmethyl)-coumarin; CA 63:5589c disclosesthe compound3-(1'-(2-methoxy,3-methyl,5-chloro-phenyl)propyl)-4-hydroxy-coumarin; CA64:12969b discloses the compound3-(α-acetonyl-α-acetylbenzyl)-4-hydroxy-coumarin.

CA 79(13):74969a; Chim. Ther. 7(4):300-6 (1972) (Fr) (CA 78(7):38016h);CA 52:5399b; CA 54:5699e; CA 54:579e; and CA 72(15):78882v disclose4-hydroxycoumarin compounds substituted at the 6- or 7-position by,e.g., methyl, methoxy and chloro.

J. M. Mulder, U.S. Pat. No. 3,835,161, 10 Sep. 1974, discloses thecompound 3- 1-4-(2-bromoethyl)phenyl!ethyl!-4-hydroxy-2H-1-benzopyran-2-one.

Merck Index, Eleventh Edition, (1989), Entry 9950, discusses Warfarin,its chemical name--3-α-phenyl-β-acetylethyl-4-hydroxycoumarin--and itsuses as a rodenticide and an anticoagulant. J. Med. Chem., 1978, Vol.21, No. 2:231-234, discloses the antivitamin K activity of warfarin anddiscusses the anticoagulant activity of several 3-substituted4-hydroxycoumarins such as 4-Hydroxy-3-(1-phenylbutyl)-coumarin; and4-hydroxy-3-(α-methylbenzyl)-coumarin. J. Am. Chem. Soc. 83:2676-9(1961) (CA 55:22306e (1961)) discusses the resolution and absoluteconfiguration of warfarin and discloses the preparation of compoundssuch as 4-hydroxy-3-(1-phenylbutyl)-coumarin.

Journal of Labelled Compounds and Radiopharmaceuticals Vol. XXIII, No.2:137-148 (1986), discloses several deuterium labelled metabolites ofwarfarin and phenprocoumon, such as the deuterium labelled analog of thecompound 4-hydroxy-7-methoxy-3-(1-phenylpropyl)-coumarin.

J48023942 discloses compounds, such as4-hydroxy-3-(α-methylbenzyl)-coumarin;4-hydroxy-3-(3-methyl-1-phenylbutyl)-coumarin; and2H-1-benzopyran-2-one, 4-hydroxy-7-methoxy-3-(1-phenylpropyl)-(alsocited in preceding reference) and their use as rodenticides.

Tr. Voronezh. Teckhnol. Inst. 19(2):27-30 (1971), Abstract No. 1zh274(Russian language), discloses the compound4-hydroxy-3-phenethylcoumarin. This reference and Helv. Chim. Acta74(7):1451-8 (1991) disclose the compound of4-hydroxy-3-(3-phenylpropyl)coumarin.

J. Org. Chem. 33(1):437-8 (1968); and Eur. J. Med. Chem.--Chim Ther.12(2):125-30 (1977) disclose compounds such as4-hydroxy-3-diphenylmethylcoumarin.

U.S. Pat. No. 3,764,693 discloses the compound4-hydroxy-3-(3-hydroxy-1-phenylbutyl)-coumarin and its anticoagulatingand rodenticidal activity.

J. Med. Chem. 18(5):513-19 (1975) (CA 83(5):37913q); J. Chromatogr.338(2):325-34 (1985); J. Chromatogr. 562 (1-2):31-8 (1991); J. LabelledCompds. Radiopharm. 23(2):137-48 (1986) (cited previously); and J.Chromatogr. 529(2):479-85 (1990) disclose compounds such as 4-hydroxy-3-1- 3-(phenylmethoxy)phenyl!propyl!-2H-1-benzopyran-2-one;4-hydroxy-8-(phenylmethoxy)-3-(1-phenylpropyl)-2H-1-benzopyran-2-one;4-hydroxy-3- 1-(4-hydroxyphenyl)propyl!-coumarin;4-hydroxy-6-methoxy-3-(1-phenylpropyl)-coumarin;4,7-dihydroxy-3-(1-phenylpropyl)-coumarin;4,6-dihydroxy-3-(1-phenylpropyl)-coumarin; 4-hydroxy-3-1-(3-hydroxyphenyl)propyl!-coumarin; and p-chlorophenprocoumon.

AIDS 1993, Vol. 7, No. 1, pages 129-130, discusses the effect ofwarfarin on HIV-1 replication and spread.

CA Selects: AIDS & Related Immunodeficiencies, Issue 24, 1993, Abstract119:195147j discloses the inhibitory effect of a single dose of coumarinderivatives, warfarin, 4-hydroxy-coumarin, umbelliferone, on HIV-1replication and cell-mediated or cell-free viral transmission.

At the First National Conference on Human Retroviruses and RelatedInfections, 12-16 Dec. 1993, Washington, D.C., it was disclosed thatcoumarins, such as warfarin, and pyrones, such as3-(thiophenyl)-6-phenyl-4-hydroxy-pyrone, displayed HIV proteaseinhibition in an assay.

Biochemical and Biophysical Research Communications, Vol. 201, No. 1,pages 290-294 (30 May 1994) discloses that warfarin and structurallyrelated coumarin analogs are HIV-1 protease inhibitors.

J. Med. Chem. 37:2664-2677 (1994) discloses4-hydroxy-3-(3-phenoxypropyl)-2H-1-benzopyran-2-one and structuralanalogs, especially 4,7-dihydroxy-3-4-(2-methoxyphenyl)butyl!-2H-1-benzopyran-2-one, as HIV-1 proteaseinhibitors.

Biochemical and Biophysical Research Communications, Vol. 200, No. 3,pages 1658-1664 (16 May 1994) discloses that4-hydroxy-3-(3-phenoxypropyl)-1-benzopyran-2-one and4-hydroxy-6-phenyl-3-(phenylthio)-pyran-2-one, and structural analogs ofthese compounds, are inhibitors of HIV-1 protease.

J. Am. Chem. Soc. 116:6989-6990 (1994) discloses4-hydroxy-6-phenyl-3-(phenylthio)pyran-2-one, and structural analogsthereof, are HIV-1 protease inhibitors.

Acta. Virol. 37:241-250 (1993) discloses the anti-HIV activity ofcoumarin derivatives, warfarin, 4-hydroxy-coumarin and umbelliferone.

Antiviral Research 24:275-288 (1994) discloses bicyclic imidazoderivatives (imidazothiazoles and imidazopyridines) which inhibit HIV-1through interaction with reverse transcriptase (RT).

U.S. Pat. No. 3,325,515 (J. Schmitt, et al.) discloses coumarinderivatives, such as 3-(4-hydroxy-3-coumarinyl)-3-phenyl-1-propionicacid methyl ester, as exhibiting anti-coagulant activity.

U.S. Pat. No. 2,723,277 (A. Grussner, et al.) discloses malonic acidderivatives, such as 3- 1'-(p-chloro-phenyl)-propyl!-4-hydroxy-coumarin,as anti-coagulant agents.

FR, A, 1276654 discloses 4-hydroxy-coumarins, such as(2'-hydroxy)-3-benzyl-4-hydroxycoumarin, which have anti-coagulant,anti-bacterial or anti-fungal properties.

BE, A, 674997 discloses 4-hydroxycoumarin derivatives, such as3-(5-methoxytetralyl-(1))-4-hydroxycoumarin as agents for fightingrodents.

GB, A, 734142 discloses the preparation of3-substituted-4-hydroxycoumarins, such as3-(1-phenyl-2-acetyl)-ethyl-4-hydroxycoumarin and3-(1-furan-2-acetyl)-ethyl-4-hydroxycoumarin, which are effective asanti-coagulants and rodenticides.

"The Application of Computer-Assisted Drug Design in the discovery ofNonpeptide HIV-1 Protease Inhibitors", Parke-Davis Pharm. Res., KeystoneSymposia, 5-11 Mar. 1994, Santa Fe, N. Mex., discloses4-hydroxy-3-(3-phenoxypropyl)-1-benzopyran-2-one as an HIV proteaseinhibitor.

Structural Biology, 1(1):199-200 (April 1994) discloses that the ratpoison warfarin was a useful lead in the search for HIV proteinaseinhibitors.

CA 85:78002b (1976) discloses3-(2,4,6-trihydroxybenzyl)-4-hydroxy-2H-pyran-2-one derivatives ashaving anti-bacterial activity.

FR, A, 1092278 (Hoffman) (1955) discloses the preparation of coumarinderivatives, such as 3- 1'-phenyl-propene-(1')-yl)-4-hydroxycoumarin.

International Publication No. WO 94/11361, published 26 May 1994,discloses pyran-2-ones and 5,6-dihydroxypyran-2-ones as retroviralprotease inhibitors.

International Publication No. WO 94/18188, published 18 Aug. 1994,discloses 4-hydroxy-benzopyran-2-ones and 4-hydroxy-cycloalkylb!pyran-2-ones as retroviral protease inhibitors.

The following references were cited against the immediate parentapplication as disclosing the state of the art:

U.S. Pat. No. 3,651,091 (Boschetti, et al.); U.S. Pat. No. 4,262,013(Mistui, et al.); U.S. Pat. No. 4,900,754 (Regan, et al.); U.S. Pat. No.5,294,724 (Jendralla, et al.); Australian Patent Specification 219,371(Enders, et al.); Canadian Patent No. 1,171,424 (Willard, et al.);British Patent Specification 836,740 (Bayer); European PatentApplication 0 024 348 (Willard, et al.); European Patent Application 0588 137 (Fischer, et al.); French Patent No. 1,276,654 (Molho) (citedabove); and International Publication No. WO 94/1136 (Thaisrivongs, etal.) (cited above).

"Collaborative Structure-Based Design of Small Organic Molecules asInhibitors of HIV Proteases," Keystone Symposia, Santa Fe, N. Mex. (5-11Mar. 1994), discloses the crystallographic complexes of HIV-1 and HIV-2protease with compounds, such as3-(α-ethylbenzyl)-6-(α-ethylphenethyl)-4-hydroxy-2H-pyran-2-one.

"Discovery and Properties of Small Organic Molecules Inhibiting HIV-1Protease," Keystone Symposia, Santa Fe, N. Mex. (5-11 Mar. 1994),discloses an assay for determining inhibitory activity of compounds,such as 3-(α-ethylbenzyl)-6-(α-ethylphenethyl)-4-hydroxy-2H-pyran-2-one.

"Structure-based Design of Non-peptide HIV Protease Inhibitors," 35thAnnual Buffalo Medicinal Chemistry Symposium, Buffalo, N.Y. (22-25 May1994), discloses compounds, such as3-(α-ethylbenzyl)-6-(α-ethylphenethyl)-4-hydroxy-2H-pyran-2-one, aspotential anti-HIV therapeutic agents.

In Hruby et. al. (J. Org. Chem., 58 (26):7567 (1993), a description ofthe copper catalyzed addition of an aryl Grignard to an unsaturatedchiral amide, 3-(2-butenoyl)-4-phenyl-2-oxazolidinone, is given. InEvans et. al. (J. Am. Chem. Soc., 112:8215 (1990), the reaction betweena chiral amide and 2-methoxy-2-methyl-1,3-dioxoline is described. Thepreparation of 2-methoxy-2-methyl-1,3-dioxoline is found in Santry et.al. (J. Am. Chem. Soc., 110 (9):2910 (1988). For references on thereaction between an ester enolate and a ketone, refer to Dongala et.al., Tetrahedron Letters, 4983 (1973), and Mitsui et. al., Tetrahedron,23:4271 (1967). For references on the reaction between an amide enolateand a ketone, refer to Viteva et. al., Tetrahedron 50:7193 (1994); Oareet. al., J. Org. Chem. 55:132 (1990); Hullot et. al., Can. J. Chem.55:266 (1977); Woodbury et. al., J. Org. Chem. 42:1688 (1977);Stefanovsky et. al., Tetrahedron 42:5355 (1986); and Mathew et. al.,U.S. Pat. No. 5,284,975.

G. Carganico, P. Cozzi, G. Orsini, J. Med. Chem., 26:1767-1769 (1983),discloses synthesized compounds with a methyl and a hydroxyl group atthe 4-position of the dihydropyrone ring and no substitution at the3-position. The compounds of the present invention have a ketone at the4-position (which may be in enol form) and substitution at the3-position.

D. T. Witiak et al., J. Med. Chem., 31:1437-1445 (1988), disclosesbenzopyran-2-ones with a hydroxy group at the 3-position. The compoundsof the present invention have alkyl substitution at that position.

B. Tait, Winter Conference on Bioorganic Medicinal Chemistry, 29 Jan.-2Feb. 1995, Steamboat Springs, Colorado, disclosed a dihydropyrone havinga phenyl group and a pentyl group at the 6-position and a --S--CH₂ --CH₂-phenyl group at the 3-position in the HIV protease area.

J. V. N. Vara Prasad, et al., J. Med. Chem., 38:898-905 (1995),discloses 4-hydroxy-6-phenyl-2-oxo-2H-pyran-3-yl)thiomethanes, such as(+)-3-cyclopentyl(cyclopentylthio)methyl!-4-hydroxy-6-phenyl-2H-pyran-2-one,as HIV-1 protease inhibitors.

SUMMARY OF THE INVENTION

The present invention provides:

A compound of the formula I

wherein R₁ is H--;

wherein R₂ is

a) C₃ -C₅ alkyl,

b) phenyl-(CH₂)₂ --,

c) het--SO₂ NH--(CH₂)₂ --,

d) cyclopropyl-(CH₂)₂ --,

e) F-phenyl-(CH₂)₂ --,

f) het--SO₂ NH-phenyl-, or

g) F₃ C--(CH₂)₂ --;

or wherein R₁ and R₂ taken together are a double bond;

wherein R₃ is the moiety of formula X

wherein R₄ is

a) phenyl,

b) het,

c) cyclopropyl,

d) H₃ C-- O(CH₂)₂ !₂ --,

e) het--SO₂ NH--,

f) Br--,

g) N₃ --, or

h) HO₃ S(CH₂)₂ --N(CH₃)--C(O)--(CH₂)₆ --C(O)--NH--;

wherein R₅ is --H;

wherein R₆ is

a) R₄ --(CH₂)_(n) --CH(R₈)--,

b) H₃ C-- O(CH₂)₂ !₂ --CH₂ --,

c) C₃ -C₅ alkyl,

d) phenyl-(CH₂)₂ --,

e) het--SO₂ NH--(CH₂)₂ --,

f) (HOCH₂)₃ C--NH--C(O)--NH--(CH₂)₃ --,

g) (HO₂ C)(H₂ N)CH--(CH₂)₂ --C(O)--NH--(CH₂)₃ --,

h) piperazin-1-yl-C(O)--NH--(CH₂)₃,

i) HO₃ S(CH₂)₂ --N(CH₃)--C(O)--(CH₂)₆ --C(O)--NH--(CH₂)₃ --,

j) cyclopropyl-(CH₂)₂ --,

k) F-phenyl-(CH₂)₂ --,

l) het--SO₂ NH-phenyl, or

m) F₃ C--(CH₂)₂ --;

wherein n is zero (0), one (1) or two (2);

wherein R₇ is

a) cyclopropyl,

b) CH₃ --CH₂ --, or

c) t-butyl;

wherein R₈ is

a) --CH₂ --CH₃, or

b) --CH₂ -cyclopropyl;

wherein R₉ is

a) --NR₁₂ SO₂ --het,

b) --NR₁₂ SO₂ -phenyl substituted by zero (0) or one (1) R₁₁,

c) --CH₂ --SO₂ -phenyl substituted by zero (0) or one (1) R₁₁, or

d) --CH₂ --SO₂ --het;

wherein het is a 5-, 6- or 7-membered saturated or unsaturated ringcontaining from one (1) to three (3) heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur; and including any bicyclicgroup in which any of the above heterocyclic rings is fused to a benzenering or another heterocycle; substituted by zero (0) or one (1) R₁₀ ;

wherein R₁₀ is

a) --CH₃,

b) --CN,

c) --OH,

d) --C(O)OC₂ H₅,

e) --CF₃,

f) --NH₂, or

g) --C(O)--NH₂ ;

wherein R₁₁ is

a) --CN,

b) --F,

c) --OH, or

d) --NO₂ ;

wherein R₁₂ is

a) --H, or

b) --CH₃ ;

or a pharmaceutically acceptable salt thereof.

The present invention more particularly provides:

A compound of the formula I

wherein R₁ is H--;

wherein R₂ is

a) C₃ -C₅ alkyl,

b) phenyl-(CH₂)₂ --, or

c) het--SO₂ NH--(CH₂)₂ --;

or wherein R₁ and R₂ taken together are a double bond;

wherein R₃ is the moiety of formula X

wherein R₄ is

a) phenyl,

b) het,

c) cyclopropyl,

d) H₃ C-- O(CH₂)₂ !₂ --,

e) het--SO₂ NH--,

f) Br--,

g) N₃ --, or

h) HO₃ S(CH₂)₂ --N(CH₃)--C(O)--(CH₂)₆ --C(O)--NH--;

wherein R₅ is --H;

wherein R₆ is

a) R₄ --(CH₂)_(n) --CH(R₈)--,

b) H₃ C-- O(CH₂)₂ !₂ --CH₂ --,

c) C₃ -C₅ alkyl,

d) phenyl-(CH₂)₂ --,

e) het--SO₂ NH--(CH₂)₂ --,

f) (HOCH₂)₃ C--NH--C(O)--NH--(CH₂)₃ --,

g) (HO₂ C)(H₂ N)CH--(CH₂)₂ --C(O)--NH--(CH₂)₃ --,

h) piperazin-1-yl-C(O)--NH--(CH₂)₃, or

i) HO₃ S(CH₂)₂ --N(CH₃)--C(O)--(CH₂)₆ --C(O)--NH--(CH₂)₃ --;

wherein n is zero (0), one (1) or two (2);

wherein R₇ is

a) cyclopropyl,

b) CH₃ --CH₂ --, or

c) t-butyl;

wherein R₈ is

a) --CH₂ --CH₃, or

b) --CH₂ -cyclopropyl;

wherein R₉ is

a) --NR₁₂ SO₂ --het,

b) --NR₁₂ SO₂ -phenyl substituted by zero (0) or one (1) R₁₁,

c) --CH₂ --SO₂ -phenyl substituted by zero (0) or one (1) R₁₁, or

d) --CH₂ --SO₂ --het;

wherein het is a 5-, 6- or 7-membered saturated or unsaturated ringcontaining from one (1) to three (3) heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur; and including any bicyclicgroup in which any of the above heterocyclic rings is fused to a benzenering or another heterocycle; substituted by zero (0) or one (1) R₁₀ ;

wherein R₁₀ is

a) --CH₃,

b) --CN,

c) --OH, or

d) --C(O)OC₂ H₅ ;

wherein R₁₁ is

a) --CN,

b) --F,

c) --OH, or

d) --NO₂ ;

wherein R₁₂ is

a) --H, or

b) --CH₃ ;

or a pharmaceutically acceptable salt thereof.

The present invention provides for such compounds wherein het is thefollowing, substituted by zero (0) or one (1) R₁₀,

a) 2-pyridinyl,

b) imidazol-2-yl,

c) imidazol-4-yl,

d) benzimidazol-2-yl,

e) quinolin-8-yl,

f) quinolin-2-yl,

g) pyrimidin-2-yl,

h) quinazolin-2-yl,

i) purin-6-yl,

j) thiazol-2-yl,

k) thiazol-4-yl,

l) 2-pyrazolyl,

m) 2-pyrazinyl,

n) tetrahydropyran-4-yl, or

o) tetrahydropyran-3-yl.

Also more particularly, the present invention provides for the compoundof the formula I

wherein R₁ is H--;

wherein R₂ is

a) H₃ C--(CH₂)₂ --,

b) phenyl-(CH₂)₂ --,

c) (CH₃)₂ CH--CH₂, or

d) pentyl;

or wherein R₁ and R₂ taken together are a double bond;

wherein R₃ is the moiety of formula X

wherein R₄ is

a) phenyl,

b) het,

c) cyclopropyl,

d) H₃ C-- O(CH₂)₂ !₂ --,

e) het--SO₂ NH--,

f) Br--,

g) N₃ --, or

h) HO₃ S(CH₂)₂ --N(CH₃)--C(O)--(CH₂)₆ --C(O)--NH--;

wherein R₅ is --H;

wherein R₆ is

a) R₄ --(CH₂)_(n) --CH(R₈)--,

b) H₃ C-- O(CH₂)₂ !₂ --CH₂ --,

c) H₃ C--(CH₂)₂ --,

d) phenyl-(CH₂)₂ --,

e) (CH₃)₂ CH--CH₂ --, or

f) pentyl;

wherein n is zero (0), one (1) or two (2);

wherein R₇ is

a) cyclopropyl, or

b) CH₃ --CH₂ --;

wherein R₈ is

a) --CH₂ --CH₃, or

b) --CH₂ -cyclopropyl;

wherein R₉ is

a) --NHSO₂ --het, or

b) --NHSO₂ -phenyl substituted by zero (0) or one (1) R₁₁ ;

wherein het is the following, substituted by zero (0) or one (1) R₁₀,

a) 2-pyridinyl,

b) imidazol-2-yl,

c) imidazol-4-yl,

d) quinolin-8-yl,

e) tetrahydropyran-4-yl,

f) tetrahydropyran-3-yl, or

g) benzimidazol-2-yl;

wherein R₁₀ is

a) --CH₃ ;

wherein R₁₁ is

a) --CN,

b) --F or

c) --NO₂ ;

or a pharmaceutically acceptable salt thereof.

Most particularly, the present invention provides for the compound ofthe formula VI

wherein R₂ is

a) H₃ C--(CH₂)₂ --,

b) phenyl-(CH₂)₂ --,

c) (CH₃)₂ CH--CH₂ --, or

d) pentyl;

wherein R₃ is the moiety of formula X

wherein R₆ is

a) H₃ C--(CH₂)₂ --,

b) phenyl-(CH₂)₂ --,

c) (CH₃)₂ CH--CH₂ --, or

d) pentyl;

wherein R₇ is

a) CH₃ --CH₂ --, or

b) cyclopropyl;

wherein R₉ is

a) --NHSO₂ -phenyl substituted by one (1) R₁₁, or

b) --NHSO₂ --het;

wherein het is the following, substituted by zero (0) or one (1) R₁₀,

a) imidazol-4-yl, or

b) quinolin-8-yl;

wherein R₁₀ is --CH₃ ;

wherein R₁₁ is

a) --CN, or

b) --F.

Also, most particularly, the present invention provides for the compoundof the formula VII

wherein R₃ is the moiety of formula X

wherein R₄ is

a) phenyl,

b) het,

c) cyclopropyl,

d) H₃ C-- O(CH₂)₂ !₂ --,

e) het--SO₂ NH--,

f) Br--,

g) N₃ --, or

h) HO₃ S(CH₂)₂ --N(CH₃)--C(O)--(CH₂)₆ --C(O)--NH--;

wherein R₆ is

a) R₄ --(CH₂)_(n) --CH(R₈)--, or

b) H₃ C-- O(CH₂)₂ !₂ --CH₂ --;

wherein R₇ is cyclopropyl;

wherein R₈ is

a) CH₂ --CH₃, or

b) --CH₂ -cyclopropyl;

wherein R₉ is

a) --NHSO₂ --het, or

b) --NHSO₂ -phenyl substituted by one (1) R₁₁ ;

wherein n is zero (0), one (1) or two (2);

wherein het is the following, substituted by zero (0) or one (1) R₁₀,

a) imidazol-4-yl,

b) imidazol-2-yl,

c) quinolin-8-yl,

d) tetrahydropyran-3-yl,

e) tetrahydropyran-4-yl,

f) 2-pyridinyl, or

g) benzimidazol-2-yl;

wherein R₁₀ is --CH₃ ;

wherein R₁₁ is

a) --NO₂,

b) --F, or

c) --CN;

or a pharmaceutically acceptable salt thereof.

The present invention also provides:

A compound of the formula II

wherein R₁₀ and R₂₀ taken together are

a) the moiety of formula III, or

b) the moiety of formula IV;

wherein p is four (4);

wherein R₁ is --H;

wherein R₂ is

a) H--,

b) CH₃ O--, or

c) CH₃ O-- (CH₂)₂ O!₃ --;

wherein R₃ is the moiety of formula V

wherein R₄ is

a) cyclopropyl, or

b) --CH₂ --CH(CH₃)₂ ;

wherein R₅ is

a) --NR₉ SO₂ -phenyl substituted by zero (0) or one (1) R₆,

b) --NR₉ SO₂ --het,

c) --CH₂ --SO₂ -phenyl substituted by zero (0) or one (1) R₆, or

d) --CH₂ --SO₂ --het;

wherein R₆ is

a) --CN,

b) --F,

c) --CH₃,

d) --COOH, or

e) --OH;

wherein het is a 5-, 6- or 7-membered saturated or unsaturated ringcontaining from one (1) to three (3) heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur; and including any bicyclicgroup in which any of the above heterocyclic rings is fused to a benzenering or another heterocycle; substituted by zero (0), one (1) or two (2)R₇ ;

wherein R₇ is

a) --CH₃,

b) --CN,

c) --C(O)OC₂ H₅, or

d) --OH;

wherein R₈ is

a) --H,

b) --(CH₂)₂ --CH₃,

c) --CH₂ -cyclopropyl, or

d) --CH₂ -phenyl;

wherein R₉ is

a) --H, or

b) --CH₃ ;

or a pharmaceutically acceptable salt thereof.

The present invention provides for such compounds wherein het is thefollowing, substituted by zero (0) or one (1) R₇,

a) 2-pyridinyl,

b) imidazol-2-yl,

c) imidazol-4-yl,

d) benzimidazol-2-yl,

e) quinolin-8-yl,

f) quinolin-2-yl,

g) pyrimidin-2-yl,

h) quinazolin-2-yl,

i) purin-6-yl,

j) thiazol-2-yl,

k) thiazol-4-yl,

l) 2-pyrazolyl,

m) 2-pyrazinyl,

n) tetrahydropyran-4-yl, or

o) tetrahydropyran-3-yl.

More particularly, the present invention provides for the compound ofthe formula II

wherein R₁₀ and R₂₀ taken together are

a) the moiety of formula III, or

b) the moiety of formula IV;

wherein p is four (4);

wherein R₁ is --H;

wherein R₂ is

a) CH₃ O--, or

b) CH₃ O (CH₂)₂ O!₃ --;

wherein R₃ is the moiety of formula V

wherein R₄ is

a) cyclopropyl, or

b) --CH₂ --CH(CH₃)₂ ;

wherein R₅ is

a) --NR₉ SO₂ -phenyl substituted by zero (0) or one (1) R₆,

b) --NR₉ SO₂ --het,

c) --CH₂ --SO₂ -phenyl substituted by zero (0) or one (1) R₆, or

d) --CH₂ --SO₂ --het;

wherein R₆ is

a) --CN,

b) --F,

c) --CH₃, or

d) --COOH;

wherein het is the following, substituted by zero (0) or one (1) R₇,

a) imidazol-4-yl,

b) quinolin-8-yl,

c) 2-pyridinyl, or

d) 4-pyridinyl;

wherein R₇ is --CH₃ ;

wherein R₈ is

a) --H, or

b) --(CH₂)₂ --CH₃ ;

wherein R₉ is

a) --H, or

b) --CH₃ ;

or a pharmaceutically acceptable salt thereof.

Most particularly, the present invention provides for the compound ofthe formula VIII

wherein R₃ is the moiety of formula V

wherein R₄ is

a) cyclopropyl,

b) --CH₂ --CH(CH₃)₂ ;

wherein R₅ is

a) --NR₉ SO₂ -phenyl substituted by zero (0) or one (1) R₆,

b) --NR₉ SO₂ --het, or

c) --CH₂ --SO₂ -phenyl;

wherein R₆ is

a) --CN, or

b) --F;

wherein het is the following, substituted by zero (0) or one (1) R₇,

a) 2-pyridinyl,

b) 4-pyridinyl, or

c) imidazol-4-yl;

wherein R₇ is --CH₃ ;

wherein R₈ is

a) --H, or

b) --(CH₂)₂ --CH₃ ;

wherein R₉ is

a) --H, or

b) --CH₃ ;

or a pharmaceutically acceptable salt thereof.

Also, most particularly, the present invention provides for the compoundof the formula IX

wherein R₁ is H--:

wherein R₂ is

a) CH₃ O--, or

b) CH₃ O-- (CH₂)₂ O!₃ --;

wherein R₃ is the moiety of formula V

wherein R₄ is cyclopropyl;

wherein R₅ is --NHSO₂ --het;

wherein het is the following, substituted by zero (0) or one (1) R₇,

a) imidazol-4-yl,

b) 2-pyridinyl, or

c) quinolin-8-yl;

wherein R₇ is --CH₃.

The present invention also provides for the compound of the formula VI

wherein R₂ is

a) H₃ C--CH₂ --,

b) H₃ C--(CH₂)₂ --,

c) cyclopropyl-(CH₂)₂ --,

d) F-phenyl-(CH₂)₂ --,

e) het--SO₂ NH-phenyl-,

f) (H₃ C)₂ HC--CH₂,

g) phenyl-(CH₂)₂ --, or

h) F₃ C--(CH₂)₂ --;

wherein R₃ is the moiety of formula X

wherein R₆ is

a) H₃ C--CH₂ --,

b) H₃ C--(CH₂)₂ --,

c) cyclopropyl-(CH₂)₂ --,

d) F-phenyl-(CH₂)₂ --,

e) het--SO₂ NH-phenyl,

f) (H₃ C)₂ HC--CH₂,

g) phenyl-(CH₂)₂ --, or

h) F₃ C--(CH₂)₂ --;

wherein R₇ is

a) H₃ C--CH₂ --,

b) t-butyl, or

c) cyclopropyl

wherein R₉ is

a) --NHSO₂ --het, or

b) --NHSO₂ -phenyl substituted by one (1) R₁₁ ;

wherein het is the following, substituted by zero (0) or one (1) R₁₀,

a) imidazol-4-yl,

b) 2-pyridinyl, or

c) quinolin-8-yl;

wherein R₁₀ is,

a) --CH₃,

b) --CN,

c) --CF₃,

d) --NH₂ or

e) --C(O)--NH₂ ;

wherein R₁₁ is CN.

The present invention also provides:

A compound of the formula XI

wherein R₁ is --(CH₂)_(p) --CH(R₂)--(CH₂)_(o) --Ar₁ ;

wherein R₂ is

a) --C₁ -C₅ alkyl, or

b) --(CH₂)_(q) -cycloalkyl;

wherein Ar₁ is

a) phenyl substituted by zero (0) or one (1) R₃, or

b) phenyl substituted by -meta-NHSO₂ Ar₂ ;

wherein Ar₂ is

a) phenyl substituted by zero (0) or one (1) R₃, or

b) het;

wherein het is a 5-, 6- or 7-membered saturated or unsaturated ringcontaining from one (1) to three (3) heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur; and including any bicyclicgroup in which any of the above heterocyclic rings is fused to a benzenering or another heterocycle; substituted by zero (0) or one (1) R₄ ;

wherein R₃ is

a) --CN,

b) --F,

c) --OH, or

d) --NO₂ ;

wherein R₄ is

a) --CH₃,

b) --CN,

c) --OH,

d) --C(O)OC₂ H₅,

e) --CF₃, or

f) --NH₂ ;

wherein n is zero (0) to eight (8), inclusive;

wherein o is zero (0) to three (3), inclusive;

wherein p is zero (0) to three (3), inclusive;

wherein q is zero (0) to three (3), inclusive; or

a pharmaceutically acceptable salt thereof.

More particularly, the present invention provides:

The compound wherein R₁ is --CH(R₂)--Ar₁ ;

wherein R₂ is

a) --CH₂ --CH₃, or

b) -t-butyl;

wherein Ar₁ is phenyl substituted by -meta-NHSO₂ Ar₂ ;

wherein Ar₂ is 2-pyridinyl substituted by one (1) R₄ ;

wherein R₄ is

a) --CN, or

b) --CF₃ ;

wherein n is two (2) to four (4) inclusive.

The present invention also provides:

A process for producing a compound of the formula W-10

wherein R₁ is

a) n-propyl, or

b) phenethyl;

which comprises the steps of:

a) treating a compound of the formula W-9

wherein X_(A) is as defined above, with TiCl₄ ;

b) treating the product of step a) with an amine base; and

c) reacting the product of step b) with 4-heptanone orpropylphenethylketone to yield the compound of formula W-10;

The process which further comprises the steps of:

d) treating the compound of formula W-10 with sodium hydride orpotassium t-butoxide to obtain a compound of formula W-11

wherein R₁ is

a) n-propyl, or

b) phenethyl;

e) hydrogenating the compound of formula W-11 to obtain the compound offormula W-12

wherein R₁ is as defined above;

f) treating the compound of formula W-12 with a sulfonyl chloride offormula D-7

wherein R₄ is 5-trifluoromethyl-2-pyridinyl, in an organic solvent inthe presence of an organic base to obtain a compound of the formula W-13

wherein R₁ is as defined above.

The present invention also provides:

A process for producing a compound of the formula X-10

wherein R₁ is

a) n-propyl, or

b) phenethyl;

which comprises the steps of:

a) treating a compound of the formula X-9

wherein X_(A) is as defined above, with TiCl₄ ;

b) treating the product of step a) with an amine base; and

c) reacting the product of step b) with 4-heptanone or

propylphenethylketone to yield the compound of formula X-10;

The process which further comprises the steps of:

d) treating the compound of formula X-10 with sodium hydride orpotassium t-butoxide to obtain a compound of formula X-11

wherein R₁ is

a) n-propyl, or

b) phenethyl;

e) hydrogenating the compound of formula X-11 to obtain a compound offormula X-12 wherein R₁ is as defined above;

f) treating the compound of formula X-12 with a sulfonyl chloride offormula D-7

wherein R₄ is 5-trifluoromethyl-2-pyridinyl, in an organic solvent inthe presence of an organic base to obtain a compound of the formula X-13

wherein R₁ is as defined above.

The present invention also provides:

A process for producing a compound of the formula GGG-10

wherein R₁ is

a) n-propyl, or

b) phenethyl;

which comprises the steps of:

a) treating a compound of the formula GGG-9

wherein X_(A) is as defined above, with TiCl₄ ;

b) treating the product of step a) with an amine base; and

c) reacting the product of step b) with 4-heptanone or1-phenyl-3-hexanone to yield the compound of formula GGG-10.

The process which further comprises the steps of:

d) treating the compound of formula GGG-10 with sodium hydride orpotassium t-butoxide to obtain a compound of formula GGG-11

wherein R₁ is

a) n-propyl, or

b) phenethyl;

e) hydrogenating the compound of formula GGG-11 to obtain a compound offormula GGG-12

wherein R₁ is as defined above;

f) treating the compound of formula GGG-12 with a sulfonyl chloride offormula D-7

wherein R₄ is

a) 5-trifluoromethyl-2-pyridinyl, or

b) 5-cyano-2-pyridinyl, in an organic solvent in the presence of anorganic base to obtain a compound of the formula GGG-13A

wherein R₁ is as defined above.

A process for producing a compound of the formula HHH-10

wherein R₁ is

a) n-propyl, or

b) phenethyl;

which comprises the steps of:

a) treating a compound of the formula HHH-9

wherein X_(A) is as defined above, with TiCl₄ ;

b) treating the product of step a) with an amine base; and

c) reacting the product of step b) with 4-heptanone or1-phenyl-3-hexanone to yield the compound of formula HHH-10.

The process which further comprises the steps of:

d) treating the compound of formula HHH-10 with sodium hydride orpotassium t-butoxide to obtain a compound of formula HHH-11

wherein R₁ is

a) n-propyl, or

b) phenethyl;

e) hydrogenating the compound of formula HHH-11 to obtain a compound offormula HHH-12

wherein R₁ is as defined above;

f) treating the compound of formula HHH-12 with a sulfonyl chloride offormula D-7

wherein R₄ is

a) 5-trifluoromethyl-2-pyridinyl, or

b) 5-cyano-2-pyridinyl, in an organic solvent in the presence of anorganic base to obtain a compound of the formula HHH-13A

wherein R₁ is as defined above.

A process for producing a compound of the formula III-10

wherein R₁ is

a) n-propyl, or

b) phenethyl;

which comprises the steps of:

a) treating a compound of the formula III-9

wherein X_(A) is as defined above, with TiCl₄ ;

b) treating the product of step a) with an amine base; and

c) reacting the product of step b) with 4-heptanone or1-phenyl-3-hexanone to yield the compound of formula III-10.

The process which further comprises the steps of:

d) treating the compound of formula III-10 with sodium hydride orpotassium t-butoxide to obtain a compound of formula III-11

wherein R₁ is

a) n-propyl, or

b) phenethyl;

e) hydrogenating the compound of formula III-11 to obtain a compound offormula III-12

wherein R₁ is as defined above;

f) treating the compound of formula III-12 with a sulfonyl chloride offormula D-7

wherein R₄ is

a) 5-trifluoromethyl-2-pyridinyl, or

b) 5-cyano-2-pyridinyl, in an organic solvent in the presence of anorganic base to obtain a compound of the formula III-13A

wherein R₁ is as defined above.

A process for producing a compound of the formula JJJ-10

wherein R₁ is

a) n-propyl, or

b) phenethyl;

which comprises the steps of:

a) treating a compound of the formula JJJ-9

wherein X_(A) is as defined above, with TiCl₄ ;

b) treating the product of step a) with an amine base; and

c) reacting the product of step b) with 4-heptanone or1-phenyl-3-hexanone to yield the compound of formula JJJ-10.

The process which further comprises the steps of:

d) treating the compound of formula JJJ-10 with sodium hydride orpotassium t-butoxide to obtain a compound of formula JJJ-11

wherein R₁ is

a) n-propyl, or

b) phenethyl;

e) hydrogenating the compound of formula JJJ-11 to obtain a compound offormula JJJ-12

wherein R₁ is as defined above;

f) treating the compound of formula JJJ-12 with a sulfonyl chloride offormula D-7

wherein R₄ is

a) 5-trifluoromethyl-2-pyridinyl, or

b) 5-cyano-2-pyridinyl, in an organic solvent in the presence of anorganic base to obtain a compound of the formula JJJ-13A

wherein R₁ is as defined above.

The present invention most preferably provides:

The compound of formula VI wherein R₂ is

a) H₃ C--(CH₂)₂ --, or

b) phenyl-(CH₂)₂ --;

wherein R₃ is the moiety of formula X;

wherein R₆ is

a) H₃ C--(CH₂)₂ --, or

b) phenyl-(CH₂)₂ --;

wherein R₇ is

a) H₃ C--CH₂ --, or

b) t-butyl;

wherein R₉ is --NHSO₂ --het;

wherein het is the following, substituted by one (1) R₁₀,

a) imidazol-4-yl, or

b) 2-pyridinyl;

wherein R₁₀ is,

a) --CH₃,

b) --CN, or

c) --CF₃.

The compounds of the present invention are named according to the IUPACor CAS nomenclature system.

The carbon atoms content of various hydrocarbon-containing moieties isindicated by a prefix designating the minimum and maximum number ofcarbon atoms in the moiety, i.e., the prefix C_(i) -C_(j) indicates amoiety of the integer "i" to the integer "j" carbon atoms, inclusive.Thus, for example, C₁ -C₃ alkyl refers to alkyl of one to three carbonatoms, inclusive, or methyl, ethyl, propyl, and isopropyl, straight andbranched forms thereof.

Also, the carbon atom content of various hydrocarbon-containing moietiesof the present invention is indicated by a subscripted integerrepresenting the number of carbon and hydrogen atoms in the moiety,e.g., "C_(n) H_(2n) " indicates a moiety of the integer "n" carbonatoms, inclusive, and the integer "2n" hydrogen atoms, inclusive. Thus,for example, "C_(n) H_(2n) " wherein n is one to three carbon atoms,inclusive, and two to six hydrogen atoms, inclusive, or methyl, ethyl,propyl and isopropyl, and all isomeric, straight and branched formsthereof.

Examples of alkyl of one to nine carbon atoms, inclusive, are methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and nonyl, and allisomeric forms thereof and straight and branched forms thereof.

Examples of alkenyl of one to five carbon atoms, inclusive, are ethenyl,propenyl, butenyl, pentenyl, all isomeric forms thereof, and straightand branched forms thereof.

By "halo" is meant the typical halogen atoms, such as fluorine,chlorine, bromine, and iodine.

The compounds of formula I and II of the present invention inhibitretroviral proteinases and thus inhibit the replication of the virus.They are useful for treating patients infected with humanimmunodeficiency virus (HIV) which results in acquired immunodeficiencysyndrome (AIDS) and related diseases.

More particularly, the compounds of the present invention are useful asnovel human retroviral protease inhibitors. Therefore, the compoundsinhibit retroviral proteases and thus inhibit the replication of thevirus. They are useful for treating human patients infected with a humanretrovirus, such as human immunodeficiency virus (strains of HIV-1 orHIV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) whichresults in acquired immunodeficiency syndrome (AIDS) and/or relateddiseases.

The capsid and replicative enzymes (i.e. protease, reversetranscriptase, integrase) of retroviruses are translated from the viralgag and pol genes as polyproteins that are further processed by theviral protease (PR) to the mature proteins found in the viral capsid andnecessary for viral functions and replication. If the PR is absent ornonfunctional, the virus cannot replicate. The retroviral PR, such asHIV-1 PR, has been found to be an aspartic protease with active sitecharacteristics similar to those exhibited by the more complex asparticprotease, renin.

The term human retrovirus (HRV) includes human immunodeficiency virustype I, human immunodeficiency virus type II, or strains thereof, aswell as human T cell leukemia virus 1 and 2 (HTLV-1 and HTLV-2) orstrains apparent to one skilled in the art, which belong to the same orrelated viral families and which create similar physiological effects inhumans as various human retroviruses.

Patients to be treated would be those individuals: 1) infected with oneor more strains of a human retrovirus as determined by the presence ofeither measurable viral antibody or antigen in the serum and 2) in thecase of HIV, having either an asymptomatic HIV infection or asymptomatic AIDS defining infection such as i) disseminatedhistoplasmosis, ii) isopsoriasis, iii) bronchial and pulmonarycandidiasis including pneumocystic pneumonia iv) non-Hodgkin's lymphomaor v) Kaposi's sarcoma and being less than sixty years old; or having anabsolute CD4+ lymphocyte count of less than 500/mm³ in the peripheralblood. Treatment would consist of maintaining an inhibitory level of thecompound used according to this invention in the patient at all timesand would continue until the occurrence of a second symptomatic AIDSdefining infection indicates alternate therapy is needed.

More specifically, an example of one such human retrovirus is the humanimmunodeficiency virus (HIV, also known as HTLV-III or LAV) which hasbeen recognized as the causative agent in human acquiredimmunodeficiency syndrome (AIDS), P. Duesberg, Proc. Natl. Acad. Sci.USA, 86:755 (1989). HIV contains a retro viral encoded protease, HIV-Iprotease, that cleaves the fusion polypeptides into the functionalproteins of the mature viral particle, E. P. Lillehoj, et al., J.Virology, 62:3053 (1988); C. Debuck, et al., Proc. Natl. Acad. Sci.,84:8903 (1987). This enzyme, HIV-I protease, has been classified as anaspartyl protease and has a demonstrated homology to other aspartylproteases such as renin, L. H. Pearl, et al., Nature 329:351 (1987); I.Katoh, et al., Nature 329:654 (1987). Inhibition of HIV-I proteaseblocks the replication of HIV and thus is useful in the treatment ofhuman AIDS, E. D. Clerq, J. Med. Chem. 29:1561 (1986). Inhibitors ofHIV-I protease are useful in the treatment of HIV-infected individualswho are asymptomatic or symptomatic of AIDS.

Pepstatin A, a general inhibitor of aspartyl proteases, has beendisclosed as an inhibitor of HIV-I protease, S. Seelmeier, et al., Proc.Natl. Acad. Sci. USA, 85:6612 (1986). Other substrate derived inhibitorscontaining reduced bond isosteres or statine at the scissle positionhave also been disclosed, M. L. Moore, et al., Biochem. Biophys, Res.Commun. 159:420 (1989); S. Billich, et al., J. Biol. Chem. 263:17905(1988); Sandoz, D. E. 3812-576-A.

Thus, the compounds of the present invention are useful for treatingdiseases caused by retroviruses, such as human acquired immunodeficiencydisease syndrome (AIDS).

The compounds are also useful for treating non-human animals infectedwith a retrovirus, such as cats infected with feline leukemia virus.Other viruses that infect cats include, for example, feline infectiousperitonitis virus, calicivirus, rabies virus, feline immunodeficiencyvirus, feline parvovirus (panleukopenia virus), and feline chlamydia.Exact dosages, forms and modes of administration of the compounds of thepresent invention to non-human animals would be apparent to one ofordinary skill in the art, such as a veterinarian.

The compounds of formula I and II of the present invention are preparedas described in the Charts, Preparations and Examples below, or areprepared by methods analogous thereto, which are readily known andavailable to one of ordinary skill in the art of organic synthesis.

CHART A

Nitration of the cyclopropylphenyl ketone of formula A-1, which iscommercially available, with fuming nitric acid at -40° C. produces aca. 2:1 mixture of isomers. The desired m-nitro compound of formula A-2is easily separated from the crude mixture by recrystallization frommethanol. Catalytic hydrogenation of thecyclopropyl-(3-nitrophenyl)methanone of formula A-2 with 10% platinum oncarbon in methanol gives the aniline of formula A-3. The aniline is thencoupled with benzenesulfonyl chloride using pyridine in methylenechloride to give the sulfonamide derivative of formula A-4. Reduction ofthe ketone with sodium borohydride in tetrahydrofuran and ethanol thenproduces the carbinol of formula A-5.

The dianion of the cyclooctylpyranone of formula A-6, prepared asdescribed in Chart B, is formed using lithium diisopropyl amide intetrahydrofuran at 0° C., and then alkylated with iodopropane to givethe 10-propyl-cyclooctylpyranone of formula A-7. The cyclooctylpyranoneof formula A-7 and the carbinol of the formula A-5 are then coupledusing p-toluenesulfonic acid in methylene chloride to give thesulfonamide derivative of formula A-8.

CHART B

The commercially available amine of the formula B-1 is protected usingbenzyl chloroformate and sodium bicarbonate in THF/water solution togive the compound of formula B-2. The aldehyde of formula B-2 is thenreacted with a Grignard reagent to give the secondary alcohol of formulaB-3, wherein, e.g., R₁ is isobutyl. The known cyclooctylpyranone offormula B-4 is prepared by acylation of the trimethylsilyl enol ether ofcyclooctanone with malonyl dichloride as described in R. Effenberger, T.Ziegler, K.-H. Schonwalder, T. Kesmarszky, B. Bauer Chem. Ber.119:3394-3404 (1986). The alcohol of formula B-3 is then used toalkylate the cyclooctylpyranone of formula B-4 in refluxing toluene andp-toluenesulfonic acid to obtain the compound of the formula B-5,wherein, e.g., R₁ is isobutyl. At this point, the enantiomers of formulaB-5 are separated using a chiral HPLC column. The benzyloxy protectinggroup is then cleaved using 10% Pd/C in cyclohexene to give the amine offormula B-6, wherein, e.g., R₁ is isobutyl, which is reacted with arylsulfonyl chlorides to give the compounds of the formula B-7, wherein,e.g., R₁ is isobutyl and R₂ is 1-methylimidazole.

CHART C

3-Bromobenzyl alcohol of formula C-1, which is commercially available,in tetrahydrofuran is treated with methyllithium, n-butyllithium andcyclopropanecarboxaldehyde in sequence at -78° C. The resulting solutionis gradually warmed to room temperature and then heated at refluxaffording the alcohol of formula C-2. The resulting alcohol, indichloromethane, in the presence of molecular sieves, is treated with4-hydroxy-5,6,7,8,9,10-hexahydrocycloocta b!pyran-2-one of formula C-8,prepared as described in Chart B, and p-toluenesulfonic acid. Thesolution is heated at reflux to afford the alcohol of formula C-3. Thebenzyl alcohol is treated with carbon tetrabromide andtriphenylphosphine in dichloromethane at 0° C. to afford compounds offormula C-4 and C-5 as an inseparable mixture after an aqueous brineworkup. The mixture is then treated with any thiol (e.g., thiophenol)and an organic base and heated at reflux to afford sulfides of theformula C-6. Finally treatment of the compounds of the formula C-6 withoxone in a mixture of tetrahydrofuran, methanol and water gives sulfonesof formula C-7.

CHART D

This chart describes a generic procedure for the preparation of C-3αbranched 5,6-dihydropyrones via aluminum chloride (AlCl₃) mediatedcondensation with 3-nitrobenzaldehyde. Thus, the AlCl₃ catalyzedreaction of the compound of formula D-1, prepared as described below inthe Preparations, (e.g., wherein R₁ is phenethyl or propyl; R₂ isphenethyl or propyl) with 3-nitrobenzaldehyde (formula D-2), which iscommercially available, provides compounds of formula D-3 (e.g., whereinR₁ is phenethyl or propyl; R₂ is phenethyl or propyl). Subsequentreaction with trialkyl aluminums or Grignard reagents in the presence ofcuprous bromide-dimethylsulfide complex (CuBr--Me₂ S) provides compoundsof formula D-4 (e.g., wherein R₁ is phenethyl or propyl; R₂ is phenethylor propyl; R₃ is ethyl or cyclopropyl). Transfer hydrogenation with Pd/Cand ammonium formate provides compounds of formula D-5 (e.g., wherein R₁is phenethyl or propyl; R₂ is phenethyl or propyl; R₃ is ethyl orcyclopropyl). Treatment of the compound of formula D-5 with sulfonylchlorides of formula D-7, wherein R₄ is defined below, and pyridine inmethylene chloride (CH₂ Cl₂) provides compounds of formula D-6 (e.g.,wherein R₁ is phenethyl or propyl; R₂ is phenethyl or propyl; R₃ isethyl or cyclopropyl; R₄ is 4-cyanophenyl, 4-fluorophenyl,1-methylimidazol-4-yl, quinolin-8-yl, 2-pyridyl, 4-cyano-2-pyridyl,quinolin-2-yl, 2-hydroxyphenyl, 2-pyrimidyl, 2-quinazoline,7H-purin-6-yl, 1H-imidazol-2-yl, 1H-benzimidazol-2-yl or thiazol-2-yl).

CHART E

Treatment of commercially available 4-hydroxy-6-methyl-2-pyrone offormula E-1 with three equivalents of lithium diisopropylamide intetrahydrofuran and hexamethylphosphoramide is followed bybromomethylcyclopropane to afford the compound of formula E-2. Reactionbetween the compound of formula E-2 and the compound of formula F-5,prepared as described in Chart F, in benzene with p-toluenesulfonic acidcatalyst in the presence of molecular sieves affords the compound offormula E-3. Hydrogenolysis of the compound of formula E-3 in methanolwith hydrogen and palladium on charcoal gives the free amine of formulaE-4. Treatment of the compound of formula E-4 with two equivalents ofpyridine in dichloromethane followed by one equivalent of4-fluorobenzenesulfonyl chloride gives the compound of formula E-5(wherein, e.g., R is 4-fluorophenyl) which is the compound:N-(3-{cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-4-fluoro-benzenesulfonamide.

Under similar conditions, compounds of general formula E-5 are obtainedby reacting amine E-4 with alkyl, aryl and heteroaryl sulfonyl chloridesin the presence of pyridine to give compounds of formula E-5 wherein Ris alkyl, aryl or heteroaryl. Also, for example, the enantiomers of thecompound of formula E-9 are separated chromatographically by chiral HPLCto give compounds of formula E-10 and E-11. Additional final compoundsof the present invention of formula E-6, E-7, E-8, and E-12-E-16 areprepared using similar conditions.

CHART F

Nitration of commercially available cyclopropyl phenyl ketone of formulaF-1 with fuming nitric acid affords the compound of formula F-2.Reduction of the compound of formula F-2 in methanol with hydrogencatalyzed by platinum on carbon gives the amine of formula F-3. Thecompound of formula F-3 is treated with benzylchloroformate anddiisopropylethylamine in dichloromethane to give the compound of formulaF-4. Reduction of the compound of formula F-4 with sodium borohydride intetrahydrofuran and ethanol gives the compound of formula F-5.

CHART G

The dianion of commercially available 4-hydroxy-6-methyl-2-pyrone offormula G-0 is generated by deprotonation with two equivalents oflithium diisopropylamide in tetrahydrofuran and hexamethylphosphoramide.Alkylation with 2-(2-methoxy-ethoxy)-ethyl iodide, which is preparedfrom the commercially available alcohol by standard procedures, givesthe compound of formula G-1. Reaction between the compound of formulaG-1 and meta-benzyloxycarbonylaminophenyl cyclopropyl carbinol, thecompound of formula F-5, prepared as described in Chart F, indichloromethane with p-toluenesulfonic acid catalyst in the presence ofmolecular sieves gives the compound of formula G-2. Hydrogenolysis ofthe compound of formula G-2 in ethanol with hydrogen and palladium oncharcoal gives the free amine of formula G-3. Treatment of the freeamine of formula G-3 with two equivalents of pyridine in dichloromethanefollowed by one equivalent of 1-methylimidazole-4-sulfonyl chloridegives the compound of formula G-4, which is the compound:N-(3-{cyclopropyl-4-hydroxy-6-(3-{2-methoxy-ethoxy}-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide.

CHART H

Reaction between commercially available 4-hydroxy-6-methyl-2-pyrone offormula H-0 and meta-benzyloxycarbonylaminophenyl cyclopropyl carbinol,the title compound of formula F-5, prepared as described in Chart F, indichloromethane with p-toluenesulfonic acid catalyst in the presence ofmolecular sieves gives the compound of formula H-1. Alkylation oftrianion of the compound of formula H-1 generated from three equivalentsof lithium diisopropylamide in tetrahydrofuran with ethyl bromideaffords the compound of formula H-2. Treatment of the compound offormula H-2 with lithium diisopropylamide in tetrahydrofuran and2-(2-methoxy-ethoxy)-ethyl iodide gives the compound of formula H-3.Hydrogenolysis of the compound of formula H-3 in ethanol with hydrogenand palladium on charcoal gives the free amine of formula H-4. Treatmentof the free amine of formula H-4 with two equivalents of pyridine indichloromethane followed by one equivalent of1-methylimidazole-4-sulfonyl chloride gives the compound of formula H-5,which is the compound: N-(3-{cyclopropyl-6-(1-ethyl-3-{2-methoxy-ethoxy}-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide.Under similar conditions, compounds of the present invention areobtained by reacting the amine of formula H-4 with alkyl, aryl andheteroaryl sulfonyl chlorides in the presence of pyridine to giveadditional sulfonamides of formula H-5.

CHART I

Treatment of the compound of formula H-2, prepared as described in ChartH, with three equivalents of lithium diisopropylamide in tetrahydrofuranand ethylene oxide gives the compound of formula I-1. Reaction of thecompound of formula I-1 with triphenylphosphine and carbon tetrabromidein tetrahydrofuran gives the compound of formula I-2. Treatment of thecompound of formula I-2 with sodium azide in aqueous ethanol gives thecompound of formula I-3. Reaction of the compound of formula I-3 withhydrogen and palladium on charcoal in ethanol gives the compound offormula I-4. Treatment of the compound of formula I-4 withdiisopropylethylamine in dichloromethane followed by1-methylimidazole-4-sulfonyl chloride gives the compound of formula I-5.Reaction of the compound of formula I-5 with ammonia in methanol givesthe compound of formula I-6, which is the compound: N-(3-{cyclopropyl-6-(1-ethyl-3-{1-methyl-1H-imidazole-4-sulfonylamino}-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide.

CHART J

Hydrogenolysis of the compound of formula I-1, prepared as described inChart I, in ethanol with hydrogen and palladium on charcoal gives thecompound of formula J-1. Treatment of the compound of formula J-1 withtriphenylphosphine and carbon tetrabromide in tetrahydrofuran gives thecompound of formula J-2. Reaction of the compound of formula J-2 withpyridine in dichloromethane followed by 1-methylimidazole-4-sulfonylchloride gives the compound of formula J-3, which is the compound:N-(3-{6-(3-bromo-1-ethyl-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-cyclopropyl-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide.Treatment of the compound of formula J-3 with sodium azide in aqueousethanol gives the compound of formula J-4, which is the compound:N-(3-{(6-(3-azido-1-ethyl-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-cyclopropyl-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide.Reaction of the compound of formula J-4 with hydrogen and palladium oncharcoal in ethanol gives the compound of formula J-5. Treatment of thecompound of formula J-5 with the triethylamine salt of suleptanic acid(Anderson, B. D.; Conradi, R. A; Knuth, K. E.; J. Pharm. Sci. 74:365(1985)) and 1,3-diisopropylcarbodiimide gives the compound of formulaJ-6, which is the compound: N-(3-{cyclopropyl- 6-(1-ethyl-3-{N-8-(methyl-{2-sulfoethyl}-amino)-1,8-dioxooctyl!amino-propyl})-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide,sodium salt.

CHART K

The preparation of the compound of formula K-8, which is the compound:N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamideis shown in Chart K. Reduction of commercially availabletetrahydropyran-4-carboxylic acid of formula K-1 with borane intetrahydrofuran provides the compound of formula K-2. The compound offormula K-2 is treated with p-toluenesulfonyl chloride to afford thecorresponding tosylate of formula K-3, which is converted to the iodideof formula K-4 by treatment with potassium iodide in refluxing acetone.Alkylation of the dianion of commercially available4-hydroxy-6-methyl-2-pyrone of formula K-10 with ethyl bromide intetrahydrofuran and hexamethylphosphoric triamide gives the propylderivative of formula K-9. The compound of formula K-4 is used toalkylate the compound of formula K-9 at the 6α position, giving thecompound of formula K-5. The compound of formula K-5 is furtheralkylated at the 3 position, using carbinol of formula F-5, prepared asdescribed in Chart F, giving the compound of formula K-6. Removal of thebenzyloxycarbonyl protecting group is accomplished using catalytictransfer hydrogenation, giving the amine of formula K-7. Treatment ofthe amine of formula K-7 with 1-methylimidazole-4-sulfonyl chloride inthe presence of pyridine provides the compound of formula K-8.

CHART L

As shown in Chart L, the dianion of commercially available4-hydroxy-6-methyl-2-pyrone of formula L-1 is generated by deprotonationwith two equivalents of lithium diisopropylamide in tetrahydrofuran andhexamethylphosphoramide. Alkylation with benzyl bromide gives thecompound of formula L-2, which is then treated with two equivalents oflithium diisopropylamide in tetrahydrofuran and hexamethylphosphoramide,followed by ethyl iodide to give the compound of formula L-3. Reactionbetween the compound of formula L-2 and the compound of formula F-5,prepared as described in Chart F, in benzene with p-toluenesulfonic acidcatalyst in the presence of molecular sieves affords the compound offormula L-4, which is 3-(3-benzyloxycarbonylaminophenyl)-cyclopropyl-methyl!-6-(1-ethylphenethyl)-4-hydroxy-2H-pyran-2-one.Hydrogenolysis of the compound of formula L-4 in methanol usingcatalytic palladium on charcoal and ammonium formate or hydrogen gasgives the free amine of formula L-5, which is 3-(3-aminophenyl)-cyclopropyl-methyl!-6-(1-ethylphenethyl)-4-hydroxy-2H-pyran-2-one.Reacting the compound of formula L-5 and the appropriate sulfonylchloride gives the final compounds of the present invention.

CHART M

As shown in Chart M, commercially available triethylene glycolmonomethyl ether is treated with p-toluenesulfonyl chloride and pyridineto provide the tosylate of formula M-2, which is then used to alkylatecommercially available 2,4-dihydroxyacetophenone to give the compound offormula M-3. Condensation with diethyl carbonate yields the compound offormula M-4. Ring closure of the compound of formula M-4 to the compoundof formula M-5 is accomplished by refluxing in acetic acid. The compoundof formula M-5 is alkylated at the 3-position using the carbinol offormula F-5, prepared as described in Chart F, and catalyticp-toluenesulfonic acid to give the compound of formula M-6. Removal ofthe benzyloxycarbonyl protecting group is accomplished using catalytictransfer hydrogenation, giving the amine of formula M-7. Treatment ofthe amine with 1-methylimidazole-4-sulfonyl chloride in the presence ofpyridine provides the final compound of formula M-8, which isN-(3-{Cyclopropyl-7-(2-(2-(2-methoxyethoxy)-ethoxy)ethoxy)-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide.

CHART N

Nitration of cyclopropylphenyl ketone of formula N-1, which iscommercially available, with fuming nitric acid at -40° C. produces aca. 2:1 mixture of isomers. The desired meta-nitro compound of formulaN-2 is easily separated from the crude mixture by recrystallization frommethanol. Catalytic hydrogenation ofcyclopropyl-(3-nitrophenyl)methanone of formula N-2 with 10% platinum oncarbon in methanol at 0° C. provides the aniline of formula N-3. Theproduct is isolated by filtration and concentration. The amino group isthen protected using benzyl chloroformate and diisopropylethylamine inmethylene chloride to give the ketone of formula N-4. The ketone is thenreduced with sodium borohydride in 5:1 THF and ethanol to give thealcohol of formula N-5.

The compound of formula N-5 is then used to alkylate4-hydroxy-5,6,7,8,9,10-hexahydrocycloocta b!pyran-2-one, which isprepared as described in R. Effenberger, T. Ziegler, K.-H. Schonzoalder,T. Kesmarsky, B. Bauer, Chem. Ber. 119:3394-3404 (1986), to give thecompound of formula N-6. The preferred conditions for this alkylationreaction are p-toluene-sulfonic acid in refluxing methylene chloridewith a Soxhlet extractor containing molecular sieves. Finally, thecompound of formula N-7 is obtained by cleaving the benzyl protectivegroup in a transfer hydrogenation. Best results for this reactions areachieved with 10% Pd/C in neat cyclohexene.

CHART O

Treatment of the amine of formula O-1, prepared as described in Chart N,with sulfonyl chlorides and a base such as pyridine in dichloromethanegives the sulfonamides of formula O-2 wherein R₆₀ is, for example,4-nitrophenyl. These sulfonamides are further modified by standardliterature procedures as is apparent to those of ordinary skill in theart to give sulfonamides of formula O-3 wherein R₆₁ is, for example,4-aminophenyl and other functional groups that are not readily availablefrom readily available sulfonyl chlorides. For example, the nitro groupof N- 3- cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-4-nitro-benzenesulfonamide is reduced bycatalytic hydrogenation in ethyl acetate with palladium on carbon togive the amine in 4-amino-N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-benzenesulfonamide. Also, the carboxylicacid of 3- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!amino!sulfonyl!-benzoic acid is esterifiedwith methanol and catalytic sulfuric acid to give the methyl ester in 3-3- cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!amino!sulfonyl!-benzoic acid, methyl ester.Sulfonamides of formula O-3 are also obtained from compounds of formulaO-2 by further elaboration of reactive functional groups. For example,the amine of 3-amino-N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-benzenesulfonamide is reacted with benzoylchloride and a base such as pyridine to give the benzamide in N- 3- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!amino!sulfonyl!henyl!-benzamide. Usingcommonly available sulfonyl chlorides, additional compounds of thepresent invention of formula II, wherein R₁₀ and R₂₀ is the moiety offormula IV, are prepared.

The sulfonyl chlorides used to make the compounds of the presentinvention are readily prepared by methods described in the literature bythose skilled in the art, as the following examples illustrate: Reactionof a suitable thiol with KHF₂ in water/methanol with chlorine gas givesthe sulfonyl fluoride (D. J. Brown, J. A. Hoskins, Aust. J. Chem.25:2641 (1972)) which is then converted into the desired sulfonylchloride (T. Norris, J. Chem. Soc., Perkin Trans. 1(11):1378 (Eng.)(1978)). Oxidation of a suitable thiol with chlorine in water withferric chloride (FeCl₃) added gives the desired sulfonyl chloride (G.Pala, Ed. Sci. 13:461 (1958); W. J. Close, J. Amer. Chem. Soc. 82:1132(1960)). Reaction of the heteroaromatic compound with fuming sulfuricacid gives a heteroaromatic sulfonic acid followed by treatment withphosphorous-oxychloride (POCl₃) and phosphorous chloride (PCl₅) givesthe desired sulfonyl chloride (V. Georgian, R. J. Harrison, L. L.Skaletzky, J. Org. Chem. 27:4571 (1962)). Reaction of a heteroaromaticcompound with manganese dioxide (MnO₂) and sodium sulfite (Na₂ SO₃) inwater gives the desired sulfonic acid followed by treatment with POCl₃and PCl₅ gives the desired sulfonyl chloride (N. A. Androva, Izvest. 455(1972); J. O. Morley, J. Chem. Comm. 88 (1976)). Treatment of theappropriate heteroaromatic chloride with sodium sulfate and HCl in watergives the desired sulfonic acid followed by treatment with POCl₃ andPCl₅ gives the desired sulfonyl chloride (T. R. Norton, J. Amer. Chem.Soc. 68:1330 (1946)). Treatment of the appropriate hydroxy compound withN,N-dimethylthiocarbonyl chloride (M. S. Newman, F. W. Hetzel, Org.Synth. Coll. Vol. IV:824 (1988); M. S. Newman, H. A. Karnes, J. Org.Chem. 31:3980 (1966)) followed by treatment of the resulting thiol, asdescribed above, gives the desired sulfonyl chloride. Treatment of theappropriately protected thio-heteroaromatic compound with chlorine inacetic acid gives the desired sulfonyl chloride (Can. J. Chem. 55:421(1977)). Using the literature procedures described above, theheteroaromatic sulfonyl chlorides of the present invention are prepared.

CHART P

The preferred procedure for the preparation of the heteroarylsulfonamides of formula P-2 is described in Chart P. Sulfonation of theamine of formula P-1, prepared in Chart N, P-1 with variousheteroarylsulfonyl chlorides of formula P-3 wherein R is, e.g.,2-pyridyl, 4-pyridyl, 5-cyanopyridin-2-yl, 2-pyrazinyl, 2-pyrimidinyl,4,6-dimethylpyrimidin-2-yl, 4-methylpyrimidin-2-yl gives thesulfonamides of formula P-2 wherein R is the corresponding substituent.

CHART Q

Generated by sequential deprotonation with sodium hydride and n-butyllithium in tetrahydrofuran at 0° C., the dianion of commerciallyavailable methyl acetoacetate is reacted with ketone of formula Q-1,prepared as described in Chart S (formula S-4). The resultingintermediate hydroxy-ester is cyclized with dilute aqueous hydroxidefollowed by aqueous hydrochloric acid to give the compound of formulaQ-2. The compound of formula Q-2 is condensed with commerciallyavailable 3-nitrobenzaldehyde in tetrahydrofuran using aluminumtrichloride as a catalyst followed by reaction of the intermediatebenzylidene adduct with triethyl aluminum in the presence of copperbromide-dimethyl sulfide to provide the compound of formula Q-3.Catalytic transfer hydrogenation with Pd/C and ammonium formate inmethanol affords the compound of formula Q-4. Treatment of the compoundof formula Q-4 with the appropriate sulfonyl chloride and pyridine indichloromethane provides the desired compound of formula Q-5 (wherein,e.g., R₁ is 5-cyano-2-pyridyl or 1-methylimidazol-4-yl).

CHART R

Catalytic hydrogenation of commercially available 3-nitropropiophenoneof formula R-1 affords the amine of formula R-2. The amine of formulaR-2 is treated with diisopropylethylamine and benzyl bromide to give thecompound of formula R-3. The dianion of methyl acetoacetate, generatedby treatment of commercially available methyl acetoacetate with sodiumhydride and n-butyl lithium in tetrahydrofuran at 0° C., is reacted withthe ketone of formula R-3. The intermediate hydroxy-ester is cyclizedwith dilute aqueous hydroxide followed by aqueous hydrochloric acid togive the compound of formula R-4. The compound of formula R-4 iscondensed with 3-nitrobenzaldehyde in tetrahydrofuran using aluminumtrichloride as a catalyst followed by reaction of the intermediatebenzylidene adduct with triethyl aluminum in the presence of copperbromide-dimethyl sulfide to provide the compound of formula R-5.Catalytic hydrogenation with Pd/C affords the diamine of formula R-6.Treatment of the compound of formula R-6 with the appropriate sulfonylchloride and pyridine in dichloromethane provides the desired compoundof formula R-7 (wherein, e.g., R₁ is 5-cyano-2-pyridyl or1-methylimidazol-4-yl).

CHART S

Commercially available 4-pentenoic acid of formula S-1 is coupled withN,O-dimethylhydroxylamine using bis(2-oxo-3-oxazolidinyl)phosphinicchloride to afford the amide of formula S-2. The amide of formula S-2 isreacted with 3-butenyl magnesium bromide in tetrahydrofuran to give theketone of formula S-3. The ketone of formula S-3 is treated with zincmetal, cuprous chloride and diiodomethane to provide the ketone offormula S-4 (also formula Q-1, see Chart Q above).

CHART T

The compound of formula T-2 (also formula D-1) (whose preparation isspecifically described in Chart D and Preparation 17 above fromcommercially available methyl acetoacetate and 1-phenyl-3-hexanone(formula T-1)) is condensed with 3-nitrobenzaldehyde in tetrahydrofuranusing aluminum trichloride as a catalyst followed by reaction of theintermediate benzylidene adduct with t-butylCu(CN)ZnI, (theorganometallic reagent derived from zinc metal, 2-iodo-2-methyl-propane,copper cyanide and lithium chloride) to provide the compound of formulaT-3. (The preparation of the organometallic reagent is further describedin the text corresponding to Preparation J above). Catalytic transferhydrogenation with Pd/C and ammonium formate in methanol affords thecompound of formula T-4. Treatment of the compound of formula T-4 withthe appropriate sulfonyl chloride and pyridine in dichloromethaneprovides the desired compound of formula T-5 (wherein, e.g., R₁ is5-cyano-2-pyridyl or 1-methylimidazol-4-yl).

CHART U

Commercially available 4-fluorohydrocinnamic acid of formula U-1 iscoupled with N,O-dimethylhydroxylamine using diethyl cyanophosphonate toprovide the amide of formula U-2. Treatment of the amide withn-propylmagnesium chloride yields the ketone of formula U-3.Condensation of the ketone with the dianion of methyl acetoacetate,followed by hydrolysis of the intermediate ester and ring closure,provides the dihydropyrone of formula U-4. Reaction of the dihydropyronewith the aldehyde of formula B-2, prepared as described in Chart Babove, in the presence of AlCl₃ provides the benzylidene compound offormula U-5; subsequent reaction with Grignard reagents or trialkylaluminums in the presence of cuprous bromide-dimethyl sulfide complexaffords compounds of formula U-6 (wherein, e.g., R₁ is ethyl,tert-butyl, or cyclopropyl). Removal of the benzyloxy-carbonyl (CBZ)protecting group is accomplished using ammonium formate and palladium oncharcoal to give the amines of formula U-7 (wherein, e.g., R₁ is ethyl,tert-butyl, or cyclopropyl). Treatment of the amines with sulfonylchlorides and pyridine in methylene chloride provides the sulfonamidesof formula U-8 (wherein, e.g., R₁ is ethyl, tert-butyl, or cyclopropyland R₂ is alkyl, aryl, or heteroaryl).

CHART V

Commercially available 4-fluorobenzaldehyde of formula V-1 is condensedwith acetone, under basic conditions, to provide1,5-Bis-(4-fluorophenyl)-penta-1,4-dien-3-one of formula V-2. Thedienone is reduced with magnesium in methanol to provide the ketone offormula V-3. The ketone of formula V-3 is converted to dihydropyroneproducts of formula V-8 using chemistry analogous to that described inChart U for the sequence of reactions from U-3 to U-8.

CHART W

Commercially available trans 2-pentenoic acid of formula W-1 isconverted to the corresponding acid chloride using oxalyl chloride inmethylene chloride to afford the product of formula W-2. The lithiumamide of formula W-3, readily available from the treatment ofcommercially available (S)-(+)-4-phenyl-2-oxazolidinone with n-butyllithium in tetrahydrofuran at -78° C., is treated with the acid chlorideof formula W-2, to give the unsaturated amide of formula W-4. Additionof the amide of formula W-4 to a tetrahydrofuran solution containingcommercially available CuBr/(CH₃)₂ S and 3-bis(trimethylsilyl)amino!phenylmagnesium chloride at -20° C. affords thecompound of formula W-5 upon acid workup (Hruby et al., J. Org. Chem.,58(26):7567 (1993)). Treatment of the aniline of formula W-5 with benzylbromide and sodium carbonate in a water/methylene chloride mixture atreflux; or, potassium carbonate in refluxing acetonitrile, affords thecompound of formula W-6. Treatment of the amide of formula W-6 withTiCl₄ followed by an amine base in a solvent such as methylene chlorideat below -20° C., preferably at -78° C., then addition of the2-methoxy-2-methyl-1,3-dioxoline of formula W-7 (prepared as describedin Santry et al., J. Am. Chem. Soc., 110(9):2910 (1988)) affords thecompound of formula W-8. Brief treatment of the compound of formula W-8with a protic acid affords the β-ketoamide of formula W-9. Furthertreatment of the compound of formula W-9 with TiCl₄ followed by an aminebase, then 4-heptanone or propylphenethylketone, affords the compound offormula W-10 wherein R₁ is n-propyl or phenethyl, respectively.Treatment of the compound of formula W-10 with sodium hydride orpreferably potassium t-butoxide, in an ether solvent then affords thepyrone of formula W-11. Hydrogenation of the compound of formula W-11using, e.g., a Pd on carbon as the catalyst, affords the compound offormula W-12. Finally, treatment of the compound of formula W-12 with asulfonyl chloride of formula D-7, wherein R₄ is5-trifluoromethyl-2-pyridinyl, in an organic solvent, such as methylenechloride, in the presence of an organic base, such as pyridine, providesthe final compound of formula W-13, wherein R₁ is n-propyl or phenethyl(when R₁ is phenethyl, it is a pair of diastereomers).

CHART X

The final (R) enantiomer of formula X-13, wherein R₁ is n-propyl orphenethyl, is prepared according to the procedures of Chart W.

CHART Y

Acetyl chloride of formula Y-1 is added to the lithium amide of formulaY-2 (also X-3), readily available from the treatment of commerciallyavailable (R)-(-)-4-phenyl-2-oxazolidinone with n-butyl lithium intetrahydrofuran at -78° C., to afford the product of formula Y-3. Thecompound of formula Y-3 is treated first with TiCl₄ in methylenechloride below room temperature, followed by the addition of a tertiaryamine base with subsequent addition of the aldehyde of formula Y-4(aldehyde of the formula Y-4 is readily available from the reaction ofcommercially available 3-aminobenzaldehyde with benzyl bromide andpotassium or sodium carbonate in either acetonitrile or awater/methylene chloride mixture) to yield the compound of formula Y-5.Addition of the amide of formula Y-5 to a tetrahydrofuran solutioncontaining commercially available CuBr/(CH₃)₂ S and ethylmagnesiumchloride at -20° C. affords the compound of formula Y-6. Alternatively,the commercially available compound of formula Y-7 is treated withoxalyl chloride to afford the compound of formula Y-8. The compound offormula Y-8 is then added to a THF solution of the compound of formulaY-2 (also X-3), readily available from the treatment of commerciallyavailable (R)-(-)-4-phenyl-2-oxazolidinone with n-butyl lithium intetrahydrofuran at -78° C., to yield the compound of formula Y-9.Reduction of the compound of formula Y-9 with iron metal in analcohol/water mixture then affords the compound of formula Y-10.Treatment of the compound of formula Y-10 with benzyl bromide andpotassium or sodium carbonate in either acetonitrile or methylenechloride/water then affords the compound of formula Y-5 which, asdescribed above, is converted to the compound of formula Y-6. Thecompound of formula Y-6 is converted to final product as described forthe conversion of the compound of the formula W-6 to the compound of theformula W-13 (wherein R₁ is propyl or phenethyl) in Chart W.

CHART Z

Preparation of the (3S) amide of formula Z-6 is accomplished in the samemanner as outlined in Chart Y above, except using the compound offormula Z-2 (also W-3). The compound of the formula Z-6 is converted tofinal product as described for the conversion of the compound of formulaX-6 to the compound of the formula X-13 (wherein R₁ is propyl orphenethyl) in Chart Z.

CHART AA

Preparation of the 3(S), 6(S) Diastereomers AA-12 and AA-14: Addition ofthe unsaturated amide of formula AA-1 (also Y-5) to a tetrahydrofuransolution containing commercially available CuBr/(CH₃)₂ S andethylmagnesium chloride at -20° C. affords the compound of formula AA-2(same as Y-6). Reduction of the compound of formula AA-2 with a metalhydride (sodium borohydride, lithium aluminum hydride) affords thecompound of formula AA-3. Oxidation of the compound of formula AA-3(Swern oxidation) affords the aldehyde of formula AA-4 which is treatedwith trimethylsilylcyanide to yield the trimethylsilyl protectedcyanohydrin of formula AA-5. Alternatively, the compound of formula AA-2is treated with trimethyl aluminum followed by N-methyl-O-methylhydroxyl amine to yield the amide of formula AA-6 which is treated withlithium aluminum hydride to yield the aldehyde of formula AA-4. Thetrimethylsilyl cyanohydrin of formula AA-5 is reacted with a strong base(e.g. n-butyl lithium) followed by the addition of chiral epoxide offormula AA-7 (also BB-12; the synthesis of which is described in ChartBB) to yield the compound of formula AA-8. The compound of formula AA-8is dissolved in methylene chloride and cooled to -78° C. and TiCl₄ isadded followed by a tertiary amine base. To that solution is addedtrimethylorthoformate followed by additional TiCl₄ which yields thecompound of formula AA-9. Treatment of the compound of formula AA-9 withbase followed by trimethylsilyl chloride, then treatment with anoxidizing agent (ozone), followed by treatment with tetrabutyl ammoniumfluoride and then either potassium tert. butoxide or sodium hydride inan ether solvent, then affords the compound of formula AA-10.Hydrogenation of the compound of formula AA-10 then affords the compoundof formula AA-11. Finally, treatment of the compound of formula AA-11with a sulfonyl chloride of formula D-7 in Chart D, wherein R₄ is, e.g.,5-trifluoromethyl-2-pyridinyl, in an organic solvent, such as methylenechloride, in the presence of an organic base, such as pyridine, providesthe final compound of formula AA-12.

Furthermore, addition of the compound of formula AA-1 to atetrahydrofuran solution containing commercially available CuBr/(CH₃)₂ Sand tertiary butylmagnesium chloride at -20° C. affords the compound offormula AA-13. The compound of formula AA-13 is converted to the finalproduct, the compound of formula AA-14, using the chemistry describedfor the synthesis of AA-12.

CHART BB

Chart BB describes the asymmetric synthesis of epoxides of formula BB-7and BB-12. Alkylation of 2-methyl-2-propen-1-ol (BB-1) with commerciallyavailable benzyl bromide provides the allylic alcohol of formula BB-2(see Lipshutz, B. H. et al.; Synthesis 1992, 191). Catalytic Sharplessepoxidation using commercially available (+) diethyl L-tartrate providesthe epoxy alcohol of formula BB-8 (see: (a) Pfenniger, A.; Synthesis1986, 89. (b) Johnson, R. A.; Sharpless, K. B. In Catalytic AsymmetricSynthesis; Ojima, I., Ed.; VCH: New York, 1993; Chapter 4.1, 103.).Alkylation of the compound of formula BB-8 with benzyl bromide (see:Lipshutz, B. H. et al.; Synthesis 1992, 191) gives the compound offormula BB-9. Reaction of the compound of formula BB-9 with commerciallyavailable ethylmagnesium bromide affords the tertiary alcohol of formulaBB-10 (see: Hanson, R. M. Chem. Rev. 1991, 91, 437). Catalytichydrogenolysis of the compound of formula BB-10 provides the diol offormula BB-11. The compound of formula BB-11 is converted to the chiralepoxide of formula BB-12 by standard methodology (for a discussion ofthe conversion of vicinal diols to epoxides see: Mitsunobu, O. InComprehensive Organic Synthesis; Trost, B. M. Ed.; Pergamon Press:Oxford, 1991; Vol. 6; Chapter 1.1, 1).

In an analogous manner, the epoxide of formula BB-7 is ultimatelyderived from the epoxy alcohol of formula BB-3, which in turn isprepared by Sharpless epoxidation of allylic alcohol BB-2 usingcommercially available (-) diethyl D-tartrate.

Alternatively, reaction of the epoxy alcohol of formula BB-8 withcommercially available 4-toluenesulfonyl chloride under standardconditions affords the tosylate of formula BB-13. Reaction of thecompound of the formula BB-13 with ethylmagnesium bromide underconditions similar to those described for the nucleophilic opening ofarenesulfonate derivatives of glycidol (see: Klunder, J. M.; Onami, T.;Sharpless, K. B. J. Org. Chem. 1989, 54, 1295) affords a mixture of thedesired epoxide of formula BB-12 and hydroxytosylate of formula BB-14.The hydroxytosylate of formula BB-14 is readily converted to epoxideBB-12 by the action of K₂ CO₃ in methanol.

CHART CC

Preparation of the 3(S), 6(R) Diastereomers CC-12 and CC-14: Thesediastereomers are prepared in a manner identical to that described inChart AA with the exception that the epoxide of formula CC-7 (same asBB-7) is used.

CHART DD

Preparation of the 3(R), 6(S) Diastereomers DD-12 and DD14: Thesediastereomers are prepared in a manner identical to that described inChart AA with the exception that the amide of formula DD-1 (same as Z-5)is used.

CHART EE

Preparation of the 3(R), 6(R) Diastereomers EE-12 and EE-14: Thesediastereomers are prepared in a manner identical to that described inChart DD with the exception that the epoxide of formula EE-7 (same asBB-7) is used.

CHART FF

The lithium amide of formula FF-2, readily available from the treatmentof commercially available (S)-(+)-4-phenyl-2-oxazolidinone with n-butyllithium in tetrahydrofuran at -78° C., is treated with acetyl chlorideof formula FF-1 to give the amide of formula FF-3.Treatment of thecompound of formula FF-3 with TiCl₄ followed by treatment with atrialkyamine followed by the addition of commercially availabletrimethylacetaldehyde affords the compound of formula FF-4. Addition ofthe amide of formula FF-4 to a tetrahydrofuran solution containingcommercially available CuBr/(CH₃)₂ S and 3-bis(trimethylsilyl)amino!phenylmagnesium chloride at -20° C. affords thecompound of formula FF-5 upon acid workup. Treatment of the aniline offormula FF-5 with benzyl bromide and sodium carbonate in awater/methylene chloride mixture at reflux; or, potassium carbonate inrefluxing acetonitrile, affords the compound of formula FF-6.

The lithium amide of formula FF-7, readily available from the treatmentof commercially available (S)-(-)-4-benzyl-2-oxazolidinone with n-butyllithium in tetrahydrofuran at -78 C., is treated with acetyl chloride offormula FF-1 to give the amide of formula FF-8.Treatment of the compoundof formula FF-8 with TiCl₄ followed by treatment with a trialkyaminefollowed by the addition of commercially available trimethylacetaldehydeaffords the compound of formula FF-9. Addition of the amide of formulaFF-9 to a tetrahydrofuran solution containing commercially availableCuBr/(CH₃)₂ S and 3- bis(trimethylsilyl)amino!phenylmagnesium chlorideat -20° C. affords a mixture of compounds of formulae FF-10a and FF-10b.Treatment of the aniline of formula FF-10b with benzyl bromide andsodium carbonate in a water/methylene chloride mixture at reflux; or,potassium carbonate in refluxing acetonitrile, affords the compound offormula FF-11 Treatment of the compound of formula FF-11 with TiCl₄ inmethylene chloride followed by the addition of a tertiary amine basethen addition of 2-methyl-2-methoxy-1,3-dioxolane affords anintermediate dioxolane (see W-8 in Chart W) which is treated with mildacid to give the compound of formula FF-12. Treatment of the compound offormula FF-12 with TiCl₄, then a tertiary amine base, followed byaddition of either 4-heptanone or 1-phenyl-3-hexanone, affords the aldolproduct of formula FF-13. Treatment of the compound of formula FF-13with either sodium hydride or potassium tert. butoxide in an ethersolvent then affords the compound of formula FF-14. The compound offormula FF-14 is then hydrogenated under an atmosphere of hydrogen inthe presence of a Pd on carbon catalyst to give the compound of formulaFF-15. Finally, treatment of the compound of formula FF-15 with asulfonyl chloride of formula D-7 in Chart D, wherein R₄ is, e.g.,5-trifluoromethyl-2-pyridinyl, in an organic solvent, such as methylenechloride, in the presence of an organic base, such as pyridine, providesthe final compound of formula FF-16, wherein R₁ is, e.g., propyl orphenethyl.

CHART GG

Intermediate of formula GG-6 and final products of formula GG-16 areprepared as described in Chart FF with the exception that the(R)-(-)-4-phenyl-2-oxazolidinone and the(R)-(+)-4-benzyl-2-oxazolidinone chiral auxiliaries are used.

CHART HH

The compound of formula HH-1 (W-6), prepared as described in Chart W, isconverted to the ester of formula HH-2 wherein R is t-Bu by addition ofpotassium t-butoxide to a solution of the compound of formula HH-1 intetrahydrofuran at 0° C. The compound of formula HH-2 wherein R is t-Bumay also be prepared from HH-1 in two steps. First, the oxazolidinonegroup is cleaved by treatment of the compound of formula HH-1 withlithium hydroxide and hydrogen peroxide at 0° C. in tetrahydrofuran andwater. Next, the acid intermediate is treated with N,N-dimethylformamidet-butylacetal in refluxing benzene to produce the ester of formula HH-2(R is t-Bu). The ester of formula HH-2 wherein R is Me is prepared byheating a mixture of titanium tetrachloride and HH-1 in methanol. Thecompound of formula HH-3 is prepared by treatment of the ester offormula HH-2 with lithium diisopropylamide or sodiumhexamethyldisilylazide to form an enolate, which is then trapped byethyl formate to give the compound of formula HH-3. Treatment of thisintermediate with tosyl chloride in 1,2-dimethoxyethane gives thecompound of formula HH-4, which is then converted to the sulfurderivative of formula HH-5 by treatment with a mixture of potassiumhydride and thiophenol in tetrahydrofuran. The compound of formula HH-5is then deprotonated using t-butyllithium in tetrahydrofuran at lowtemperature. Addition of the epoxide of formula HH-6 (BB-7), prepared asdescribed in Chart BB, and an equivalent of boron trifluoride diethyletherate affords the compound of formula HH-7. This intermediate iscyclized to the compound of formula HH-8 in situ, or it is isolated andtreated with sodium hydride in tetrahydrofuran to produce the cycliccompound of the formula HH-8. The sulfur group is then hydrolyzed usingeither sodium hydroxide in acetonitrile or aqueous copper chloride togive the dihydropyrone derivative of formula HH-9. The benzyl protectinggroups are then removed by catalytic hydrogenation using 10% palladiumon carbon in ethyl acetate. The resulting amine of formula HH-10 isconverted to the desired sulfonamide derivative of formula HH-11 bytreatment with 5-cyanopyridine-2-sulfonyl chloride, prepared using themethods described in Chart O, and pyridine in dichloromethane.

CHARTS II-OO

The diastereomer of formula II-7 is prepared according to Chart II byprocedures analogous to those described for the preparation of thediastereomeric product in Chart HH. Likewise, stereoisomers of formulaeJJ-11, KK-7, LL-11, MM-7, NN-11, and OO-7 are prepared according toCharts JJ, KK, LL, MM, NN, and OO, respectively, by procedures analogousto those described in Chart HH.

CHART PP

The compound of formula PP-4 (HH-8) is also generated as described inChart PP. The acid of formula PP-2 is prepared by treatment of thet-butyl ester of formula PP-1 (HH-5), prepared as described in Chart HH,with aqueous acid. The compound of formula PP-2 is then treated witht-butyllithium in tetrahydrofuran at low temperature to produce adianionic intermediate, which is treated with the epoxide of formulaPP-3 (BB-7), prepared as described in Chart BB, and an equivalent ofboron trifluoride diethyl etherate to afford the compound of formulaPP-4 (HH-8).

CHARTS QQ-WW

The diastereomer of formula QQ-3 (II-4) is prepared according to ChartQQ by procedures analogous to those described for the preparation of thediastereomeric product in Chart PP. Likewise, stereoisomers of formulaeRR-4 (JJ-8), SS-3 (KK-4), TT-4 (LL-8), UU-3 (MM-4), VV-4 (NN-8), andWW-3 (OO-4) are prepared according to Charts RR, SS, TT, UU, VV, and WW,respectively, by procedures analogous to those described in Chart PP.

CHART XX

The compound of formula XX-6 (HH-9) is also generated as described inChart XX. The compound of formula XX-1 (HH-2), prepared as described inChart HH, is heated neat in commercially-availabletris(dimethylamino)methane, bis(dimethylamino)-methoxymethane ort-butoxy-bis(dimethylamino)methane to generate the intermediate offormula XX-2. One equivalent of t-butyllithium is added to a solution ofthis ester in tetrahydrofuran at low temperature to produce an anionicintermediate, which is treated with the epoxide of formula XX-3 (BB-7),prepared as described in Chart BB, and an equivalent of borontrifluoride diethyl etherate to afford the compound of formula XX-4. Theintermediate of formula XX-4 is cyclized to the dihydropyroneintermediate XX-5 in situ, or XX-4 is isolated and cyclized by treatmentwith potassium t-butoxide or sodium hydride in tetrahydrofuran.Likewise, intermediate XX-5 is hydrolyzed in situ to form the compoundof formula XX-6 (HH-9), or it is isolated and converted to thedihydropyrone of formula XX-6 (HH-9) by treatment with aqueous acid oraqueous base.

CHARTS YY-EEE

The diastereomer of formula YY-5 (II-5) is prepared according to ChartYY by procedures analogous to those described for the preparation of thediastereomeric product in Chart XX. Likewise, stereoisomers of formulaeZZ-6 (JJ-9), AAA-5 (KK-5), BBB-6 (LL-9), CCC-5 (MM-5), DDD-6 (NN-9), andEEE-5 (OO-5) are prepared according to Charts ZZ, AAA, BBB, CCC, DDD,and EEE, respectively, by procedures analogous to those described inChart XX.

CHART FFF

The diastereomers of formulae FFF-5 and FFF-7 are also prepared byseparation of a diastereomeric intermediate. The diastereomeric mixtureof formula FFF-1 (W-11), prepared as described in Chart W, is separatedinto the single diastereomers of formulae FFF-2 (less polardiastereomer) and FFF-3 (more polar diastereomer) using a preparativechiral HPLC column. The benzyl protecting groups of compounds FFF-2 andFFF-3 are then removed by catalytic hydrogenation using 10% palladium oncarbon in ethyl acetate to form the amines of formulae FFF-4 and FFF-6,respectively. The amine intermediates are then converted to the desiredsulfonamide derivatives of formulae FFF-5 (HH-11) and FFF-7 (II-7),respectively, by treatment with 5-cyanopyridine-2-sulfonyl chloride,prepared using the methods described in Chart O, and pyridine indichloromethane.

CHART GGG

The m-nitrocinnamic acid chloride (available from the treatment of thecommercially available acid with oxylal chloride) of formula GGG-1 isadded to an ether solution of the lithiooxazolidinone of formula GGG-2(readily available from the treatment of commercially available(R)-(+)-4-benzyl-2-oxazolidinone with n-butyl lithium) to afford thecompound of formula GGG-3. The compound of formula GGG-3 is treated witheither SnCl₂.2H₂ O in ethanol or iron powder in a mixture ofethanol/water and containing ammonium chloride, to effect the reductionof the nitro group to the corresponding amine found in the compound offormula GGG-4. The compound of formula GGG-4 is treated with excessbenzyl bromide in the presence of potassium or sodium carbonate in anorganic solvent (with methylene chloride/water also being added) toyield the compound of formula GGG-5. Addition of a THF solution of thecompound of formula GGG-5 to a THF/dimethylsulfide mixture containingthe cuprate reagent prepared from ethyl magnesium bromide and copperbromide/dimethyl sulfide complex affords the compound of formula GGG-6.The compound of GGG-6 is then treated with TiCl₄, then a tertiary amine,followed by the addition of 2-methyl-2-methyoxy-1,3-dioxolane of formulaGGG-7 to yield the compound of formula GGG-8. Treatment of the compoundof formula GGG-8 with perchloric acid then yields the compound offormula GGG-9. Alternately, the compound of formula GGG-6 is treatedwith a strong base such lithium diisopropylamide in an ether solventbelow room temperature and added to a solution of acetyl chloride (alsoin an ether solvent and cooled to below room temperature) to yield thecompound of formula GGG-9. The compound of formula GGG-9 is treated withTiCl₄ in methylene chloride followed by the addition of a tertiaryamine, then addition of either 4-heptanone or 1-phenyl-3-hexanone toyield the compound of formula GGG-10. The compound of formula GGG-10 isthen treated with either sodium hydride or potassium tert-butoxide in anether solvent to yield the compound of formula GGG-11. The compound offormula GGG-11 is then hydrogenated to yield the compound of formulaGGG-12. The compound of formula GGG-12 is then converted to the finaltitle compound by treatment with a sulfonyl chloride of formula D-7 inChart D, wherein R₄ is, e.g., 5-trifluoromethyl-2-pyridinyl, in anorganic solvent, such as methylene chloride, in the presence of anorganic base, such as pyridine, provide the final compound of formulaGGG-13, wherein R₁ is, e.g., n-propyl or phenethyl.

Alternatively, addition of the compound of formula GGG-5 to aTHF/dimethylsulfide solution containing a mixture of tert-butylmagnesium chloride and copper bromide/dimethylsulife complex at below 0°C. yields a mixture of compounds of formulae GGG-14a and GGG-14b. Boththe compounds of formula GGG-14a and GGG-14b are converted to the finalproducts GGG-19 and GGG-20 using the methodology described in Chart GGGfor the synthesis of the C-3 ethyl compound of formula GGG-13.

CHART HHH

The final compounds of formula HHH-13, HHH-19 and HHH-20 are prepared inthe same manner as described for the final compounds in Chart GGG.

CHART III

The commercially available acid of formula III-1 is converted to thecompound of formula III-2 by treatment with oxalyl chloride. The acidchloride of formula III-3 is then coupled to the lithio oxazolidinone offormula III-3 (readily available from the treatment of commerciallyavailable (S)-(-)-4-benzyl-2-oxazolidinone with n-butyl lithium in anether solvent) to yield the compound of formula III-4. Addition of theamide of formula III-4 to a tetrahydrofuran solution containingcommercially available copper bromide/dimethyl sulfide complex and 3-bis(trimethylsilyl)amino!phenylmagnesium chloride at -20° C. affords thecompounds of formula III-5a and III-5b upon acid workup. These compoundsare separable by silica gel chromatography. The compound of formulaIII-5a is treated with benzyl bromide in either acetonitrile or amethylene chloride/water mixture in the presence of either potassium orsodium carbonate to yield the compound of formula III-6. The compound offormula III-6 is treated with TiCl₄ in methylene chloride followed bythe addition of a tertiary amine and then2-methyl-2-methoxy-1,3-dioxolane of formula III-7 is added to yield thecompound of formula III-8. Treatment of the compound of the formulaIII-8 with an acid such as perchloric acid then yields the compound offormula III-9. Treatment of the compound of formula III-9 with TiCl₄ inmethylene chloride then addition of a tertiary amine, followed by theaddition of either 4-heptanone or 1-phenyl-3-hexanone then affords thecompound of formula III-10. Treatment of the compound of formula III-10with either sodium hydride or potassium tert. butoxide then affords thecompound of formula III-11. The compound of formula III-11 ishydrogenated to afford the compound of formula III-12. Finally,treatment of the compound of formula III-12 with a sulfonyl chloride offormula D-7 in Chart D, wherein R₄ is, e.g.,5-trifluoromethyl-2-pyridinyl, in an organic solvent, such as methylenechloride, in the presence of an organic base, such as pyridine, providesthe final compound of formula III-13, where in R₁ is, e.g., propyl orphenethyl.

In an analogous fashion, starting with the compound of formula III-5b,the final compound of formula III-14 is also prepared.

CHART JJJ

The final compounds of formula JJJ-13 and JJJ-14 are prepared using themethodology described in Chart III.

CHART KKK

The compound of formula KKK-1 (same as JJJ-9) is treated with TiCl₄ inmethylene chloride followed by the addition of a tertiary amine. To thatsolution is added commercially available hydrocinnamaldehyde to affordthe compound of formula KKK-2. The compound of formula KKK-2 is oxidized(e.g. Me₂ SO--SO₃ /pyridine) to yield the compound of formula KKK-3. Thecompound of formula KKK-3 is treated with propylmagnesium chloride(where R₁ is, e.g., phenyl) to yield the compounds of formula KKK-4a andKKK-4b. Depending on the specific reaction conditions, the ratio ofKKK-4a/KKK-4b varies. Alternatively, addition of allylzinc bromide orallylsilane in the presence of TiCl₄ or n-Bu₄ NF (see Taniguchi et. al.Chemistry Letters 2135, 1992) to the compound of formula KKK-3, followedby hydrogenation, also yields the compounds of formula KKK-4a andKKK-4b. Depending on the specific reaction conditions the ratio ofKKK-4a and KKK-4b vary. The compound of KKK-4a is treated with eithersodium hydride or potassium tert. butoxide to yield the compound offormula KKK-5. It is also possible that upon treatment of KKK-3 withallyl zinc bromide, allyl silane or propylmagnesium chloride theintermediate metal alkoxide (metals being magnesium, zinc and titanium)will undergo spontaneous cyclization to yield an unsaturatedintermediate which upon hydrogenation leads directly to KKK-5 withoutthe isolation of KKK-4a. The compound of formula KKK-5 is hydrogenatedto yield the compound of formula KKK-6. Finally, treatment of thecompound of formula KKK-6 with a sulfonyl chloride of formula D-7 inChart D, wherein R₄ is, e.g., 5-trifluoromethyl-2-pyridinyl, in anorganic solvent, such as methylene chloride, in the presence of anorganic base, such as pyridine, provides the final compound of formulaKKK-7a, wherein, e.g., R₁ and R₂ are phenyl or propyl, respectively.

In an analogous manner to that described for the conversion of thecompound of formula KKK-4a to the compound of formula KKK-7a, thecompound of formula KKK-4b is converted to the final product of formulaKKK-7b.

In an analogous manner to that described for the conversion of thecompound of formula KKK-1 to final products of the formula KKK-7a andKKK-7b, the compounds of formula KKK-14a and KKK-14b, wherein R₁ and R₂are, e.g., methyl or phenethyl, respectively, are prepared by startingwith the compound of formula KKK-8 (same as III-6).

In an analogous manner to that described for the conversion of thecompound of formula KKK-1 and the compound of formula KKK-8 (eachcontaining the 4-benzyl-2-oxazolidinone auxillary) to the final productsof the formulae KKK-7a and KKK-7b, and the final formulae KKK-14a andKKK-14b respectively, the compounds of the formula KKK-15 and thecompound of the formula KKK-19 (each containing the4-phenyl-2-oxazolidinone auxillary) are converted to the final productsof the formula KKK-7a and K-7b, and the final products of formulaKKK-14a and KKK-14b, respectively, wherein R₁ and R₂ are, e.g., methylor phenethyl, respectively.

CHART LLL

The compound of formula LLL-1 (same as: wherein R is phenyl, AA-1;wherein R is benzyl, GGG-5) is added to a THF solution of commerciallyavailable copper bromide/dimethylsulfide complex and tert.butylmagnesium chloride below 0° C. to afford the compound of formulaLLL-2 as the major diasteromeric product. Where R is defined as benzylin the compound of formula LLL-2, that compound is treated with TiCl₄ inmethylene chloride below 0° C. followed by the addition of a tertiaryamine, then the addition of 2-methyl-2-methoxy-1,3-dioxolane to yieldthe compound of formula LLL-3. The compound of formula LLL-3 is treatedwith a protic acid to afford the compound of formula LLL-4. The compoundof formula LLL-4 is treated with TiCl₄ in methylene chloride below 0° C.followed by the addition of an amine base, then addition of either4-heptanone or 1-phenyl-3-hexanone affords the compound of formula LLL-5wherein R₁ is, e.g., n-propyl or phenethyl, respectively. Treatment ofthe compound of formula LLL-5 with either sodium hydride or potassiumtert. butoxide in an ether solvent affords the pyrone of formula LLL-6.Hydrogenation of the compound of formula LLL-6 using, e.g. a Pd oncarbon as the catalyst, affords the compound of formula LLL-7. Finally,treatment of the compound of formula LLL-7 with a sulfonyl chloride offormula D-7 in Chart D, wherein R₄ is, e.g.,5-trifluoromethyl-2-pyridinyl, in an organic solvent, such as methylenechloride, in the presence of an organic base, such as pyridine, providesthe final compound of formula LLL-8, wherein R₁ is, e.g., propyl orphenethyl.

The compound of formula LLL-2, where R is phenyl, is treated with TiCl₄in methanol to yield the compound of formula LLL9. The compound offormula LLL-9 is treated with a base to effect hydrolysis to give thecompound of formula LLL-10. The acid of formula LLL-10 is treated withmethyl lithium in an ether solvent to yield the compound of formulaLLL-11. The ketone of formula LLL-11 is treated with TiCl₄ in methylenechloride below 0° C. followed by the addition of an amine base, thenaddition of either 4-heptanone or 1-phenyl-3-hexanone, to give thecompound of formula LLL-12 wherein R₁ is, e.g., n-propyl or phenethyl,respectively. The compound of formula LLL12 is treated with TiCl₄ inmethylene chloride below 0° C. followed by the addition of an aminebase, then the addition of trimethyl orthoformate to yield the compoundof formula LLL-13. The compound of formula LLL-13, in an organic solventsuch as THF or methylene chloride, is treated with a base followed bythe addition of trimethylsilyl chloride. The solvent is removed from theaforementioned reaction and the resulting protected tertiary alcohol isoxidized (e.g. Ru cat./t-BuOH (see Murahashi et. al. Chemistry Letters2237, 1992); tritylperchlorate/methylene chloride (see Mukaiyama et. al.Chemistry Letters 1255, 1985), ozone/methylene chloride (see Can. J.Chem. 49, 2465, 1971)) to afford the lactone LLL-6 directly or in a twostep sequence where the intermediate ester is lactonized with the aid ofeither sodium hydride, potassium tert. butoxide or n-Bu₄ NF in an ethersolvent. The conversion of the compound of formula LLL-6 to the finalproduct is described above.

Following the same strategy the compound of formula LLL-16 is convertedto the final products of formula LLL-23 wherein R₁ is propyl orphenethyl.

CHART MMM

The diastereomers of formulae MMM-5 and MMM-7 are also prepared byseparation of a diastereomeric mixture of these two compounds.Alternatively, the diastereomeric mixture of formula MMM-1 (X-11 whereR₁ is, e.g., phenethyl) prepared as described in Chart X, is separatedinto the single diastereomers of formulae MMM-2 and MMM-3 using apreparative chiral HPLC column. The benzyl protecting group groups ofcompounds MMM-2 (less polar diastereomer) and MMM-3 (more polardiastereomer) are then removed by catalytic hydrogenation using 10%palladium on carbon in ethyl acetate to form the amines of formulaeMMM-4 and MMM-6, respectively. The amine intermediates are thenconverted to the desired sulfonamide derivatives of formulae MMM-5 andMMM-7, respectively, by treatment with5-trifluoromethyl-2-pyridinylsulfonyl chloride, prepared using themethods described in Chart O, and pryidine in methylene chloride.

CHART NNN

The commercially available (1R,2S)-(-)ephedrine of formula NNN-2 istreated with triethylamine and the acid chloride of formula NNN-1 (W-2),prepared as described in Chart W, to afford the amide of formula NNN-3.A t-butyl methyl ether solution of this amide at 0° C. is treatedsequentially with 1.1 equivalents of propyl magnesium chloride and 2.0equivalents of 3- bis(trimethylsilyl)amino!phenyl magnesium chloride,stirred for 3 hours at 0° C., washed with ammonium chloride solution andconcentrated in vacuo. The residue is then stirred with silica gel inchloroform to afford the compound of formula NNN-4. Alternatively, theabove reaction mixture may be washed with 1N hydrochloric acid solutionduring the workup instead of ammonium chloride solution to generate thecompound of formula NNN-4. The amine is then converted to the derivativeof formula NNN-5 by heating a mixture of the compound of formula NNN-4,2.2 equivalents of benzyl bromide and 2.2 equivalents of sodiumcarbonate in acetonitrile. The intermediate of formula NNN-5 is thentreated with 2 equivalents of lithium diisopropylamide intetrahydrofuran to form the lithium enolate, which is trapped withacetyl chloride to afford the b-ketoamide of formula NNN-6. A solutionof this amide in methylene chloride at low temperature may be treatedwith 1 equivalent of titanium tetrachloride and 1 equivalent ofdiisopropylethylamine, followed by 4-heptanone to generate the compoundof formula NNN-7. Conversion of the amide of formula NNN-7 to thedihydropyrone of formula NNN-8 may be accomplished with either sodiumhydride in tetrahydrofuran or with aqueous acid. The benzyl protectinggroups may then be removed by catalytic hydrogenation using 10%palladium on carbon in ethyl acetate. The resulting amine of formulaNNN-9 is converted to the desired sulfonamide derivative of formulaNNN-10 (W-12) by treatment with 5-trifluoromethylpyridine-2-sulfonylchloride, prepared using the methods described in Chart O, and pyridinein dichloromethane.

CHART OOO

The compound of formula OOO-7 (NNN-8) may also be generated as describedin Chart OOO. The amide of formula OOO-1 (NNN-5) is treated with aqueousacid to afford the compound of formula OOO-2. The methyl ester offormula OOO-3 is formed from the compound of formula OOO-2 usingcatalytic acid in methanol. Treatment of the methyl ester of formulaOOO-3 with lithium diisopropylamide, followed by trimethylsilyl chloridegives the compound of formula OOO-4. Treatment of this intermediate witheither 2-methoxy-2-methyl-1,3-dioxolane followed by hydrolysis ortreatment with acetyl chloride affords the β-keto ester of formulaOOO-5. This β-keto ester is converted to the compound of formula OOO-6by treatment of either the titanium enolate (formed using 1 equivalentof titanium tetrachloride and 1 equivalent of diisopropylethylamine inmethylene chloride at low temperature) or the lithium dianion (formedusing 2 equivalents of lithium diisopropylamide in tetrahydrofuran atlow temperature) with 4-heptanone. The dihydropyrone of formula OOO-7(NNN-8) is formed by treatment of the compound of formula OOO-6 witheither sodium hydride in tetrahydrofuran or aqueous base.

CHART PPP

Reduction of the commercially available ethyl 4,4,4-trifluorobutyrate offormula PPP-1, with DiBAL-H followed by in situ alkylation with2-phenethyl magnesium bromide or chloride produces the alcohol offormula PPP-2. Swern oxidation of the alcohol gives the ketone offormula PPP-3. The ketone is converted to the dihydropyrone of formulaPPP-4 by alkylation with the dianion of methyl acetoacetate followed bysaponification to the acid and lactonization with base.

CHART QQQ

The aluminum trichloride catalyzed reaction of the dihydropyrone offormula QQQ-1 (PPP-4), prepared as described in Chart PPP, with theCBZ-protected 3-aminobenzaldehyde (which is available from the reactionof benzyl chloroformate with commercially available 3-aminobenzaldehyde)of formula QQQ-2 and subsequent reaction with trialkyl aluminums orGrignard reagents in the presence of cuprous bromide-dimethylsulfidecomplexes provides compounds of formula QQQ-3. The individualstereoisomers are separated by HPLC using a chiral stationary phase togive the four possible stereoisomers of formula QQQ-4, QQQ-5, QQQ-6, andQQQ-7. Transfer hydrogenation of each stereoisomer with Pd/C andammonium formate gives the amines of formula QQQ-8, QQQ-9, QQQ-10, andQQQ-11. Treatment of the amines with sulfonyl chlorides of generalformula QQQ-12 and pyridine in methylene chloride provides compounds ofgeneral formula QQQ-13, QQQ-14, QQQ-15, and QQQ-16, wherein R₂ is, e.g.,5-cyano-2-pyridinyl, 1-methyl-4-imidazolyl, or 5-amino-2-pyridinyl.

CHART RRR

The procedure for the preparation of compounds of formula RRR-11 toRRR-15 is described in Chart RRR. The pyrone RRR-A is coupled to the Cbzprotected benzaldehyde RRR-B in THF with AlCl₃ followed by treatment ofthe resulting intermediate with R₁ MgX where X═Br or Cl in THF withadded CuBr.Me₂ S to give RRR-1. De-protection of the resultingintermediate with 10% Pd/C in methanol with added ammonium formate givesRRR-2. Separation of the racemic compound RRR-1 into its 4 enantiomersgives RRR-3 to RRR-6. De-protection of the resulting intermediates with10% Pd/C in methanol with added ammonium formate gives the free aminesRRR-7 to RRR-10. Treatment of the amines RRR-7 to RRR-10 and RRR-2 withan appropriate sulfonyl chloride gives the sulfonamides RRR-11 to RRR-14and RRR-15, respectively.

CHART SSS

The procedure for the preparation of compounds of formula SSS-7 to SSS-9is described in Chart SSS. The pyrone SSS-A is coupled to the Cbzprotected benzaldehyde SSS-B in THF with AlCl₃ followed by treatment ofthe resulting intermediate with R₁ MgX where X═Br or Cl in THF withadded CuBr.Me₂ S to give SSS-1. De-protection of the resultingintermediate with 10% Pd/C in methanol with added ammonium formate givesSSS-2. Separation of the racemic compound SSS-1 into its 2 enantiomersgives SSS-3 to SSS-4. De-protection of the resulting intermediates with10% Pd/C in methanol with added ammonium formate gives the free aminesSSS-5 to SSS-6. Treatment of the amine with an appropriate sulfonylchloride gives the sulfonamides SSS-7 to SSS-9.

CHART TTT

The procedure for the preparation of compounds of formula TTT-6 andTTT-7 is described in Chart TTT. The pyrone TTT-A is coupled to the Cbzprotected benzaldehyde TTT-B in THF with AlCl₃ followed by treatment ofthe resulting intermediate with R₁ MgX where X═Br or Cl in THF withadded CuBr.Me₂ S to give TTT-1. Separation of the racemic compound TTT-1into its 2 enantiomers gives TTT-2 and TTT-3. De-protection of theresulting intermediates with 10% Pd/C in methanol with added ammoniumformate gives the free amines TTT-4 and TTT-5. Treatment of the aminewith an appropriate sulfonyl chloride gives the sulfonamides TTT-6 andTTT-7.

CHART UUU

Reaction between commercially available thiourea in hot ethanol withcommercially available 2-chloro-5-nitropyridine of formula UUU-1 affordsthe isothiourea compound of formula UUU-2. Treatment of the compound offormula UUU-2 with aqueous sodium carbonate and sodium hydroxideprovides the thiol compound of formula UUU-3. Oxidation of the compoundof formula UUU-3 with chlorine gas provides the sulfonyl chloridecompound of formula UUU-4. Treatment of the compound of formula D-5(e.g., the compound of formula T-4 wherein R₁ is 2-phenylethyl, R₂ ispropyl, R₃ is tert-butyl) in dichloromethane with two equivalents ofpyridine followed by one equivalent of the compound of formula UUU-4gives the sulfonamide compound of formula UUU-5 (wherein R₁ is2-phenylethyl, R₂ is propyl, R₃ is tert-butyl). Reduction of thecompound of formula UUU-5 with palladium on carbon and ammonium formateaffords the compound of formula UUU-6, which is the compound: 5-amino-N-3-(1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide(Formula UUU-6: R₁ is 2-phenylethyl, R₂ is propyl, R₃ is tert-butyl).

CHART VVV

The compound of Formula VVV-1, which is 2-mercapto-5-carbamoylpyridine,is prepared via published procedure (J. Chem. Soc. 1948, 1939-1945).Treatment of a suspension of this compound in dilute hydrochloric acidwith chlorine gas at 0° provides the sulfonyl chloride of Formula VVV-2.

CHART WWW

Amines of the generic formula WWW-1 are reacted with benzylchloroformate to provide CBZ derivatives WWW-2. The individualstereoisomers of formula WWW-2 are generally separated by chiral HPLCmethods, and then converted back to the free amines WWW-3 viahydrogenolysis. Sulfonation of the amines in the usual manner known toone of ordinary skill in the art provides the final compounds of formulaWWW-4, in stereochemically pure form.

CHART XXX

Dihydropyrone XXX-1, which is prepared by procedures analogous to thosein described in Preparations 17 and 84, is condensed withmeta-nitrobenzaldehyde in the presence of aluminum trichloride toprovide the benzylidene intermediate XXX-2. Conjugate reduction of thedouble bond using sodium cyanoborohydride, followed by reduction of thenitro group via catalytic hydrogenation, affords amine of formula XXX-4,which is converted to the sulfonamides XXX-5 by treatment with theappropriate sulfonyl chloride in dichloromethane and pyridine.

CHART YYY

Dihydropyrones of Formula YYY-1, wherein R₁ and R₂ are propyl orphenethyl, and which are synthesized as described in Preparation 84, arecondensed with the aldehyde of Formula B-2 using aluminum trichloride toprovide the benzylidene intermediates of formula YYY-2. Conjugateaddition of tert-butylmagnesium chloride in the presence of copper (I)bromide-dimethyl sulfide provides compounds of Formula YYY-3.Hydrogenolytic deprotection affords amines of formula YYY-4, which areconverted to the sulfonamides of formula YYY-5 using the appropriatesulfonyl chloride in dichloromethane with added pyridine. The proceduresused are analogous to those described for Chart D.

CHART ZZZ

Polymeric meta-aminobenzaldehyde is protected by treating with benzylbromide and potassium carbonate in acetonitrile at reflux to yield thecompound of formula ZZZ-2. A vinyl anion is generated from2-bromovinyltrimethylsilane of formula ZZZ-3 by treatment with t-butyllithium at -78° C. to -20° C. The vinyl anion so generated is cooled to-78° C. and the diprotected meta-aminobenzaldehyde of formula ZZZ-2 isadded to afford the desired allylic alcohol of formula ZZZ-3. Thealcohol is easily converted to the acetate or carbonate of formula ZZZ-5by standard means (e.g., CH₃ COCl, pyridine, CH₂ Cl₂, 0° C.). Thesesubstrates participate in palladium catalyzed allylic substitutions asdelineated in Charts AAAA-CCCC (C. G. Frost; J. Howarth; J. M. J.Williams, Tetrahedron: Asymmetry (1992) 3:1089-1122).

CHART AAAA

The sodium salt of methyl acetoacetate of formula AAAA-1 generated bytreating methyl acetoacetate with sodium hydride at 0° C. in either DMFor THF acts as the nucleophile in a palladium catalyzed allylicsubstitution. If this reaction is run in the presence of palladium allylchloride dimer of formula AAAA-3 as the palladium source and a chiralphosphine ligand (P. von Matt; A. Pfaltz, Angew. Chem. Int. Ed. Engl.(1993) 32:566-568), a kinetic resolution of the starting allylic acetateor carbonate results in the synthesis of optically enriched allylatedproduct of formula AAAA-4. If the reaction with nucleophile is slow, theacetate generated from formation of the pi-allyl palladium intermediateisomerizes the two possible diastereomeric pi-allyl complexes so that astereoselective synthesis of the allylated product occurs (B. M. Trost;P. E. J. Strege, Am. Chem. Soc. (1977) 99:1649). Treatment of theresulting vinyl silane of formula AAAA-4 with para-toluenesulfonic acidin acetonitrile at reflux affords the desilylated olefin of formulaAAAA-5. The dihydropyrone product of formula AAAA-7 is formed bygenerating the dianion of the β-ketoester under standard conditions (J.R. Peterson; T. J. Winger; C. P. Miller, Syn. Comm. (1988)18(9):949-963), (NaH, n-butyllithium, THF) and quenching with anappropriate symmetrical ketone of formula AAAA-6 (such as 4-heptanone).Hydrolysis of the ester (0.1N NaOH/THF) and acidic work-up provide thedihydropyrone product of formula AAAA-7. Standard hydrogenationconditions reduce the olefin and deprotect the amine. Subsequenttreatment of the amino compound with the appropriate sulfonyl chlorideof formula AAAA-8 (pyridine, CH₂ Cl₂) provides the desired sulfonamideprotease inhibitor of formula AAAA-9.

CHART BBBB

Alternatively, the palladium catalyzed allylic substitution may beperformed with the sodium anion of the requisite dihydropyrone J. R.(Peterson; T. J. Winger; C. P. Miller, Syn. Comm. (1988) 18(9):949-963)of formula BBBB-1 (dihydropyrone, NaH, THF or DMF, 0° C.) as thenucleophilic partner. Once again, if palladium allyl chloride dimer offormula BBBB-3 and a chiral phosphine ligand (P. von Matt; A. Pfaltz,Angew. Chem. Int. Ed. Engl. (1993) 32:566-568) are employed as catalyst,a kinetic resolution results in the synthesis of optically pureallylated dihydropyrone of formula BBBB-4; and a stereoselectivesynthesis of the allylated product will occur if the reaction withnucleophile is slow relative to isomerization of the two possiblediastereomeric pi-allyl complexes by acetate generated from formation ofthe pi-allyl palladium intermediate. Subsequent, desilylation (p-TsOH,CH₃ CN), olefin reduction and amine deprotection (H₂ /Pd/C), andsulfonylation of the amine (ArSO₂ Cl, pyridine, CH₂ Cl₂) with a compoundof the formula BBBB-5 provides the desired dihydropyrone proteaseinhibitor of formula BBBB-6.

CHART CCCC

Treatment of m-bis(benzyl)aminobenzoic acid of formula CCCC-1 withoxalyl chloride to form the acid chloride and reaction withbis(trimethylsilyl)acetylene and AlCl₃ in methylene chloride affords thepropargylic ketone of formula CCCC-2. Asymetric reduction of the ketonewith a chiral borane (H. C. Brown; Beeraraghavan Ramachandran, P. Acc.Chem. Res. (1992) 25:16-24) such as DIP chloride (+) or(-)-β-chlorodiisopinocampheylborane! and acetylene reduction with REDALprovides the allylic alcohol of formula CCCC-3, primarily as a singleenantiomer. Formation of the carbonate of formula CCCC-4 (methylchloroformate, pyridine, CH₂ Cl₂, 0° C.) and subjection to palladiumcatalyzed allylic substitution with the desired dihydropyrone of formulaCCCC-5 as nucleophile affords primarily one enantiomer of the allylateddihydropyrone of formula CCCC-6 (retention of configuration) (T.Hayashi; T. Hagihara; M. Konishi; M. J. Kumada, Am. Chem. Soc. (1983)105:7768-7770). This product is transformed into the desired proteaseinhibitor of formula CCCC-7 as previously described in Chart BBBB.

CHART DDDD

The known cycloalkylpyranones of formula DDDD-1 are prepared byacylation of the trimethylsilyl enol ether of the correspondingcycloalkyl ketone with malonyl dichloride as described in R.Effenberger, T. Ziegler, K.-H. Schonwalder, T. Kesmarszky, B. BauerChem. Ber. 119:3394-3404 (1986). Catalytic hydrogenation of thecycloalkylpyranones of formula DDDD-1 with platinum oxide (PtO₂) inacetic acid produces the cycloalkyldihydropyrones of Formula DDDD-2. Theintermediate of formula DDDD-3 is then formed by aluminum chloride(AlCl₃) catalyzed condensation of the compound of formula DDDD-2 with3-nitrobenzaldehyde, which is commercially available. Subsequentreaction of the intermediate of formula DDDD-3 with trialkyl aluminumsin the presence of copper bromide-dimethyl sulfide complex (CuBr--Me₂ S)or zinc reagents generated from zinc metal, alkyl halide, cuprouscyanide (CuCN) and lithium chloride (LiCl) provides compounds of formulaDDDD-4 which contain a C-3a branched substituent. Catalytichydrogenation of compounds of the formula DDDD-4 with Pd/C in ethanol(EtOH) provides the amine derivatives of the formula DDDD-5. Treatmentof the compounds of formula DDDD-5 with sulfonyl chlorides of formulaDDDD-6 and pyridine in methylene chloride (CH₂ Cl₂) provides compoundsof the formula DDDD-7 (e.g., wherein n is 1, 2, or 3; R₁ is ethyl ort-butyl; R₂ is 4-cyanophenyl or 5-cyano-2-pyridyl).

Procedures by which the compounds of the present invention are preparedare also described in International application, PCT/US93/10645, filed 9Nov. 1993 (WO 94/11361, published 26 May 1994), and Internationalapplication, PCT/US94/00938, filed 3 Feb. 1994 (WO 94/18188, published18 Aug. 1994), both of which are incorporated by reference herein.

As is apparent to those of ordinary skill in the art, the compounds ofthe present invention can occur in several diastereomeric forms,depending on the configuration around the asymmetric carbon atoms. Allsuch diastereomeric forms are included within the scope of the presentinvention.

Also, the dihydropyrones of the present invention can be separated intoindividual stereoisomers or prepared as individual diastereomers. Adiastereomeric pair can be prepared wherein C-3α is a homogeneous centerand C-6 is a mixture. All such enantiomeric and diastereomeric forms,and mixtures thereof, are included within the scope of the presentinvention.

The compounds of the present invention of formula I can exist in severaltautomeric forms, including the particular enol forms as depicted byformula I and IA and the keto form of formula IB. (For formulas I, IAand IB, the dashed line indicates that a double bond may be present orabsent.) All such tautomeric forms are included within the scope of thepresent invention. For compounds of the present invention which are4-hydroxy-pyran-2-ones of formula VII, the enol form predominates. Forcompounds of the present invention which are5,6-dihydro-4-hydroxy-pyran-2-ones of formula VI, a mixture of the enoland keto forms is commonly expected.

Also, the compounds of the present invention of formula II can exist inseveral tautomeric forms of the 4-hydroxy-pyrone ring, including theparticular enol forms depicted by formulas II and IIA, and theparticular keto form depicted by formula IIB, and mixtures thereof. Allsuch tautomeric forms are included within the scope of the presentinvention.

The compounds of the present invention may be in either free form or inprotected form at one or more of the remaining (not previouslyprotected) carboxyl, amino, hydroxy, or other reactive groups. Theprotecting groups may be any of those known in the art. Examples ofnitrogen and oxygen protecting groups are set forth in T. W. Greene,Protecting Groups in Organic Synthesis, Wiley, New York, (1981); J. F.W. McOmie, ed. Protective Groups in Organic Chemistry, Plenum Press(1973); and J. Fuhrhop and G. Benzlin, Organic Synthesis, Verlag Chemie(1983). Included among the nitrogen protective groups aret-butoxycarbonyl (BOC), benzyloxycarbonyl, acetyl, allyl, phthalyl,benzyl, benzoyl, trityl and the like.

The present invention provides for compounds of formula I and II orpharmacologically acceptable salts and/or hydrates thereof.Pharmacologically acceptable salts refers to those salts which would bereadily apparent to a manufacturing pharmaceutical chemist to beequivalent to the parent compound in properties such as formulation,stability, patient acceptance and bioavailability. Examples of salts ofthe compounds of formula I include acidic salts, such as sodium,potassium, lysine, arginine and calcium salts, and basic salts, such asthe hydrochloride salt, wherein the R substituents in formula I containa basic moiety. Examples of salts of the compounds of formula II includethe hydrohalide salts, such as the hydrochloride and hydroiodide salts;and the sodium, potassium, calcium, lysine and arginine salts.

Also included as salts of the compounds of formulae I and II of thepresent invention are the bis-salts, such as the bis-arginine,bis-lysine, bis-sodium, bis-potassium and bis-calcium salts, providedthat the compound contains, for example, --NHSO₂ --, --SO₃ H, --CONH--,--OH or COOH. The bis-sodium salt is most preferred.

The compounds of the present invention are useful for treating patientsinfected with human immunodeficiency virus (HIV) which results inacquired immunodeficiency syndrome (AIDS) and related diseases. For thisindication, these compounds may be administered by oral, intranasal,transdermal, subcutaneous and parenteral (including intramuscular andintravenous) routes in doses of 0.1 mg to 100 mg/kg of body weight perday.

Those skilled in the art would know how to formulate the compounds ofthis invention into appropriate pharmaceutical dosage forms. Examples ofthe dosage forms include oral formulations, such as tablets or capsules,or parenteral formulations, such as sterile solutions.

When the compounds in this invention are administered orally, aneffective amount is from about 0.1 mg to 100 mg per kg of body weightper day. Either solid or fluid dosage forms can be prepared for oraladministration. Solid compositions, such as compressed tablets, areprepared by mixing the compounds of this invention with conventionalingredients such as talc, magnesium stearate, dicalcium phosphate,magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia,methyl cellulose, or functionally similar pharmaceutical diluents andcarriers. Capsules are prepared by mixing the compounds of thisinvention with an inert pharmaceutical diluent and placing the mixtureinto an appropriately sized hard gelatin capsule. Soft gelatin capsulesare prepared by machine encapsulation of a slurry or solution of thecompounds of this invention with an acceptable inert oil such asvegetable oil or light liquid petrolatum.

Pharmaceutically acceptable formulations of the disodium salts of thecompounds of the present invention include: soft elastic capsules (SEC)containing a suspension of the salt; salt tablets; salt spray coatedsucrose beads; or salt spray dried matrix with an enteric or non-entericpolymer.

Formulations of the compounds of the present invention, which presentthe compounds in free acid form, preferably contain the free acid innon-crystalline form. Examples of such formulations include: softelastic capsules containing free acid solution; non-crystalline spraydried matrix of the free acid with an enteric or non-enteric polymer; ora solid non-crystalline matrix of free acid in polyethyleneglycol (PEG)or Gelucire 44/14 (Gattefosse, Saint Priest, France).

Syrups are prepared by dissolving the compounds of this invention in anaqueous vehicle and adding sugar, aromatic flavoring agents andpreservatives. Elixirs are prepared using a hydroalcoholic vehicle suchas ethanol, suitable sweeteners such as sugar or saccharin and anaromatic flavoring agent. Suspensions are prepared with an aqueousvehicle and a suspending agent such as acacia, tragacanth, or methylcellulose.

When the compounds of this invention are administered parenterally, theycan be given by injection or by intravenous infusion. An effectiveamount is from about 0.1 mg to 100 mg per kg of body weight per day.Parenteral solutions are prepared by dissolving the compounds of thisinvention in liquid vehicle and filter sterilizing the solution beforeplacing in a suitable sealable vial or ampule. Parenteral suspensionsare prepared in substantially the same way except a sterile suspensionvehicle is used and the compounds of this invention are sterilized withethylene oxide or suitable gas before it is suspended in the vehicle.

The exact route of administration, dose, or frequency of administrationwould be readily determined by those skilled in the art and is dependanton the age, weight, general physical condition, or other clinicalsymptoms specific to the patient to be treated.

Patients to be treated would be those individuals: 1) infected with oneor more than one strain of a human immunodeficiency virus as determinedby the presence of either measurable viral antibody or antigen in theserum and 2) having either an asymptomatic HIV infection or asymptomatic AIDS defining infection such as i) disseminatedhistoplasmosis, ii) isoporiasis, iii) bronchial andpulmonary-candidiasis including pneumocystis pneumonia, iv)non-Hodgkin's lymphoma, or v) Kaposi's sarcoma and being less than sixtyyears old; or having an absolute CD4+ lymphocyte count of less than500/mm³ in the peripheral blood. Treatment would consist of maintainingan inhibitory level of the compounds of this invention in the patient atall times and would continue until the occurrence of a secondsymptomatic AIDS defining infection indicates alternate therapy isneeded.

The utility of representative compounds of the present invention hasbeen demonstrated in the biological tests described below:

The HIV protease screening assay is based on fluorescently labeledsubstrate which can be resolved from nonlabeled cleavage product usingspecial beads coated with streptavidin. The substrate is biotinylated atthe amino terminal arginine and fluorescently labeled with fluoresceinisothiocynate (FITC) at the carboxyl terminal lysine. This assay hasbeen employed to detect novel, nonpeptidic inhibitors of HIV-1 protease.Substrate (20 μl of 0.2 μM), sample (10 μl of desired concentration),and enzyme (10 μl of 0.1 μM) are added to a 96 well pandex plate. Theassay is run in 0.1M sodium acetate buffer at pH 5.5 in the presence of1.0M sodium chloride and 0.05% NP-40 with incubated in the dark for onehour at room temperature. Streptavidin coated polystyrene beads {40 μlof 0.1% (w/v)} are added and the plate is incubated in the dark for anadditional half hour. The labeled cleavage product is separated from theunreacted substrate via filtration and is read on the Idexx screenmachine. The data are analyzed by appropriate computer algorithms toascertain percent inhibition values.

Determination of K_(i) values utilizes the same materials and equipmentemployed for percent inhibition studies. Two-fold serial dilutions aremade for a given inhibitor from 2, 3 or 4 starting concentrations with atotal of 24, 36 or 48 individual inhibitor concentrations. Thesedilutions are performed utilizing the BioMek robotics system. The assayconsists of 10 μL of 40 nM HIV-1 protease, 10 μL of the variousinhibitor concentrations, and 20 μL of 200 μM substrate (40 uL total).The reaction is allowed to proceed for 90 min at room temperature,terminated with 40 μL of avidin beads and processed (supra vide). Aninhibitor with a known K_(i) is run in parallel to verify the validityof the assay. The data is processed utilizing a computer programemploying a nonlinear least square analysis of the data to generate theK_(i) values.

The % inhibition values and/or K_(i) values of representative compoundsof the present invention tested in the HIV protease screening assay arelisted in Table I below.

In the enzyme inhibition assay described above, the sensitivity of K_(i)value determination is in part limited by the ability to continue tolower the enzyme concentration for compounds with high binding affinity.To prevent de-dimerization at low enzyme concentration, a tandemlylinked enzyme is prepared in which the two monomers are covalentlylinked by an appropriate stretch of amino acid residues. Using thelatter enzyme, the sensitivity of the inhibition assay is improved sincemuch lower enzyme concentration can be utilized, as compared to thecondition using the wild-type enzyme.

Protocol for K_(i) value determination with tandem HIV protease: Due tothe greater stability (no dedimerization) of the single chain tethered(tandem) HIV protease enzyme, in which the two monomeric units areengineered to be linked by a polypeptide stretch, the method for thedetermination of K_(i) values for inhibitors uses very lowconcentrations of enzyme (0.2 nM) and increased incubation times (96hours) at room temperature to improve the sensitivity in the measurementof K_(i) values for very potent inhibitors. The starting inhibitorconcentrations are determined based on preliminary enzyme inhibitionscreening results which estimate the expected potency of the inhibitor.Inhibitor concentrations are then prepared using the Biomek 1000(Beckman) and the Quadra 96 (Tomtec). Substrate (biotinylated at theamino terminal arginine and fluorescently labeled with fluorescein atthe carboxyl terminal lysine), inhibitor and the tandem enzyme areallowed to react in solution at pH 5.5 (buffers identical to those usedwith the native dimeric enzyme) in the dark for 96 hours. Streptavidincoated polystyrene beads are added to stop the reaction. The labeledcleavage product is separated from unreacted substrate via filtration.Residual fluorescence is quantitated with the Idexx SM2000 (Idexx) andthe resulting data are analyzed using the NLLSF program.

The % inhibition values and/or K_(i) values of representative compoundsof the present invention tested in the HIV protease screening assayand/or tandem HIV protease assay are listed in Table II below.

Several compounds of the present invention, such as N- 3-(1-5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamidewere tested in known human cell lines, such as human T-cell lines, e.g.,MT4 and H9, which were infected with HIV-1_(IIIB), and certain of thesecompounds were further tested in peripheral blood mononuclear cells(PBMC), which were infected with HIV-1_(JRCSF) (a clinical isolate). Thecompounds were found to inhibit retroviral replication.

The following compounds of the present invention are preferred:

5-Cyano-N- 3-(1-5,6-dihydro-4-hydoxy-2-oxo-6-(2-phenethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide

N- 3-(1-5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide

N- 3-1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl)phenyl!-5-cyanopyridine-2-sulfonamide

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-(4-fluorophenyl)ethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-(4-fluorophenyl)ethyl)-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-(4-fluorophenyl)ethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide

N- 3-(1-6,6-Bis-(2-cyclopropyl-ethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethyl-propyl)phenyl!-5-cyano-2-pyridinesulfonamide

N- 3-(1-6,6-Bis-(2-cyclopropyl-ethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!propyl)phenyl!-5-cyano-2-pyridinesulfonamide

N- 3-(1-6,6-Bis-(2-cyclopropyl-ethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethyl-propyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide

5-cyano-N- 3-(R or S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R orS)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

N- 3-(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6-(R orS)-(2-phenethyl)-6-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

5-amino-N- 3-(R or S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R orS)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

N- 3-(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)- 6-(R orS)-propyl!-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide

5-Trifluoromethyl-N- 3- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,or (3R or S)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide

5-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide, or (3Ror S, 6R or S)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide

5-Amino-N- 3-(1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Cyano-N- 3(R or S)-(1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Cyano-N- 3-(1-5,6-dihydro-6,6-diisobutyl-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

N- 3(R or S)- 1-(5,6-Dihydro-4-hydroxy-2-oxo-6(R or S)-2-phenylethyl!-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

5-Cyano-N- 3-(1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!cyclopropylmethyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(R or S)-(1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(R or S)-(1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(R or S)-(1- 6(R or S)-(2-4-fluorophenyl!ethyl)-5,6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

N- 3(R or S)-(1-5,6-Dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

5-Amino-N- 3(R or S)-(1-5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Cyano-N- 3(R or S)-(1-5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

N- 3(R or S)-(1-6,6-Bis(2-phenylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!propyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N- 3(R or S)-(1-6,6-Bis(2-phenylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!propyl)phenyl!-5-cyano-2-pyridinesulfonamide,

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S orR)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N- 3-{1(S orR)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-aminopyridine-2-sulfonamide

N- 3-{1(S orR)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide

N- 3-{1(S orR)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide

N- 3-{1(R orS)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide

The following compounds of the present invention are more preferred:

5-Cyano-N- 3-(1-5,6-dihydro-4-hydoxy-2-oxo-6-(2-phenethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide

5-cyano-N- 3-(R or S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R orS)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,or (3R or S)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide

5-Trifluoromethyl-N- 3(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide, or (3Ror S, 6R or S)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide

5-Cyano-N- 3(R or S)-(1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

N- 3(R or S)- 1-(5,6-Dihydro-4-hydroxy-2-oxo-6(R or S)-2-phenylethyl!-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S orR)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,and

N- 3-{1(R orS)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide.

The following compounds of the present invention are most preferred (seeChart EEE):

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S orR)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamideof formula EEE-1,

N- 3-{1(R orS)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamideof formula EEE-2,

N- 3(R or S)- 1-(5,6-Dihydro-4-hydroxy-2-oxo-6(R or S)-2-phenylethyl!-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamideof formula EEE-3,

5-Trifluoromethyl-N- 3(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide offormula EEE-4, or (3R or S, 6R or S)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide

5-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamideof formula EEE-5, or (3R or S)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide.

Also the following compounds of the present invention, which are readilyprepared by the synthetic procedures set out herein, are most preferred:

(3R)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide

(3R)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the Preparations and Examples below and throughout this document:

°C. is degrees Centigrade.

¹ H-NMR is proton nuclear magnetic resonance spectrum.

¹³ C-NMR is carbon nuclear magnetic resonance spectrum.

δ is chemical shift (parts per million) relative to TMS.

AlCl₃ is aluminum chloride.

Anal. is analytical data.

Br is benzyl.

CBZ is benzyloxycarbonyl.

CDCl₃ is deuterio-chloroform.

CD₃ OD is deuterio-methanol.

CH₂ Cl₂ is methylene chloride.

cm⁻¹ is reciprocal centimeters.

CuBr₂ is cupric bromide.

DMSO is dimethylsulfoxide.

DMSO_(D6) is deuterio dimethylsulfoxide.

EI MS is electron impact mass spectroscopy.

EtOAc is ethyl acetate.

Et₃ Al is triethyl aluminum.

FAB MS is fast-atom-bombardment mass spectroscopy.

HCl is hydrochloric acid.

H₂ O is water.

HOBT is 1-hydroxybenzotriazole hydrate.

HRMS is high-resolution mass spectroscopy.

KOH is potassium hydroxide.

M is molar (concentration).

MeOH is methanol.

Me₂ S is dimethyl sulfide.

mg is milligram.

MgSO₄ is magnesium sulfate.

mL is milliliter.

mmHg is millimeter of mercury.

MP is melting point.

N is normal (concentration).

NaCl is sodium chloride.

NaOH is sodium hydroxide.

NaH is sodium hydride.

NaHCO₃ is sodium bicarbonate.

Na₂ CO₃ is sodium carbonate.

Na₂ SO₄ is sodium sulfate.

NH₄ Cl is ammonium chloride.

Pd/C is palladium on charcoal.

R_(f) is chromatographic movement relative to solvent front.

TFA is trifluoroacetic acid.

THF is tetrahydrofuran.

TMS is tetramethyl silane.

The following Preparations and Examples illustrate the presentinvention:

PREPARATION 1

Cyclopropyl-(3-nitrophenyl)methanone (Formula A-2) Refer to Chart A

A 500-mL, three-necked, round-bottomed flask with a gas outlet and a250-mL pressure-equalizing addition funnel is charged with cyclopropylphenyl ketone of formula A-1 (30 mL) and cooled to -40° C. The additionfunnel is charged with nitric acid (180 mL), which is added to thereaction mixture dropwise over 2 h. The reaction mixture is stirredanother 3.5 h at -40°-0° C., and then quenched by pouring onto 500 mL ofice. The mixture is extracted with three 150-mL portions of ethylacetate. The organic layers are combined, washed with two 250-mLportions of saturated sodium bicarbonate, dried over magnesium sulfate,filtered, and concentrated to give 41.117 g of yellow solid in an orangeoil. Recrystallization from 65 mL of methanol yields 20.664 g of thetitle product as light yellow crystals.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ8.85, 8.43, 8.33, 7.70, 2.72, 1.36-1.31, 1.20-1.14 ppm.

PREPARATION 2

Cyclopropyl-(3-aminophenyl)methanone (Formula A-3) Refer to Chart A

A 500-mL Parr hydrogenation flask is charged with 2.1 g of 10% platinumon carbon and a solution of the title product of Preparation 1 (20.6 g)in 250 mL of methanol. The reaction mixture is shaken for 50 min under44 psi of hydrogen, then filtered through Celite twice. The light greensolution is then concentrated to give 15.744 g of the title product as agreen oil.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.42, 7.30-7.23, 6.88, 3.83, 2.63, 1.24-1.19, 1.05-0.99ppm.

PREPARATION 3

N- 3-cyclopropylmethanone!benzenesulfonamide (Formula A-4) Refer toChart A

A 500-mL, three-necked, round-bottomed flask with a nitrogen inlet ischarged with the title product of Preparation 2 (15.7 g) and 200 mL ofmethylene chloride. Benzenesulfonyl chloride (12 mL) and pyridine (7.8mL) are added, and the reaction mixture is stirred at room temperaturefor 45 min. 10% HCl (200 mL) is added to quench the reaction. Theorganic layer is separated, dried over magnesium sulfate, filtered, andconcentrated to give 28.638 g of orange solid. Recrystallization from 75mL of hot methylene chloride yields the title product (22.264 g) as apink solid.

Physical characteristics are as follows:

MP 98°-101° C.

¹ H NMR (CDCl₃) δ7.81-7.73, 7.62, 7.55-7.35, 2.60, 1.30-1.25, 1.10-1.03ppm,

¹³ C NMR (CDCl₃) δ200.4, 138.8, 137.2, 133.0, 129.5, 129.0, 127.0,125.1, 124.7, 120.5, 17.3, 12.1 ppm.

IR (mineral oil) 3239, 3222, 1653, 1449, 1339, 1259, 1176, 1165, 1093,939, 687 cm⁻¹.

Elemental analysis, found: C, 63.70; H, 5.01; N, 4.78.

MS (EI) m/e 301, 260, 160, 141, 77.

For high resolution, found: 301.0772.

PREPARATION 4

N- 3-cyclopropylmethanol!benzenesulfonamide (Formula A-5) Refer to ChartA

A 500-mL, three-necked, round-bottomed flask with a nitrogen inlet ischarged with the title compound of Preparation 3 (21.133 g), 200 mL oftetrahydrofuran, and 100 mL of ethanol. The flask is cooled to 0° C. inan ice bath, and sodium borohydride (10.6 g) is added in small portionsover 20 minutes. The reaction mixture is stirred at room temperature forca. 18 h, and then cooled again in an ice bath to 0° C. 10% HCl (100 mL)is added dropwise over 45 min, and the mixture is stirred another 1 h at0° C. The reaction mixture is then extracted with three 100-mL portionsof methylene chloride. The organic layers are combined, dried overmagnesium sulfate, filtered and concentrated to give 25.015 g of paleyellow oil. Column chromatography on 150 g of silica gel (elution with50-65% ether in hexane followed by 2-5% methanol in methylene chloride)yields 18.692 g of the title product as a white solid.

Physical characteristics are as follows:

MP 112°-114° C.

¹ H NMR (CDCl₃) δ7.69, 7.42, 7.32, 7.25, 7.12, 7.05-6.96, 3.82, 3.19,1.03-0.94, 0.51-0.46, 0.39-0.29, 0.19-0.16 ppm.

¹³ C NMR (DMSO) δ147.0, 139.7, 137.4, 132.9, 129.3, 128.6, 126.8, 121.8,118.5, 117.8, 75.0, 19.2, 3.1, 2.3 ppm.

IR (mineral oil) 3523, 3249, 1449, 732 cm⁻¹.

Elemental analysis, found: C, 63.41; H, 5.79; N, 4.86.

MS (EI) m/e 303, 275, 262, 77.

For high resolution, found: 303.0935.

PREPARATION 5

4-Hydroxy-10-propyl-2H-cycloocta b!pyran-2-one (Formula A-7) Refer toChart A

A 250-mL, three-necked, round-bottomed flask with a nitrogen inlet and a125-mL pressure-equalizing addition funnel is charged with diisopropylamine (3.6 mL) and 15 mL of tetrahydrofuran. The addition funnel ischarged with 4-hydroxy-2H-cycloocta b!pyran-2-one of formula A-6 (2.292g) and 35 mL of tetrahydrofuran. The flask is cooled to 0° C. in an icebath, n-butyllithium (16.3 mL of 1.6M solution in hexanes) is addeddropwise over 3 min, and the reaction mixture is stirred another 15 minat 0° C. The solution of 4-hydroxy-2H-cycloocta b!pyran-2-one in THF isadded dropwise over 35 min, and the reaction mixture is stirred foranother 25 min at 0° C. Hexamethylphosphoramide (4 mL) is added in oneportion, and iodopropane (1.3 mL) is added dropwise over 2 min. Thereaction mixture is allowed to warm to room temperature and stirred forca. 18 h. 30 mL of 10% HCl is added and the aqueous layer is separated.The pH of the aqueous layer is lowered from 10 to 2 with concentratedHCl, and the aqueous layer is extracted with two 50-mL portions ofmethylene chloride. The organic layers are combined, dried overmagnesium sulfate, filtered, and concentrated to give an orange oil,which is partitioned between 100 mL of 1N sodium hydroxide and 50 mL ofether. The aqueous layer pH is adjusted from 14 to 1 with concentratedhydrochloric acid, and is then extracted with two 50-mL portions ofmethylene chloride. The organic layers are then combined, dried overmagnesium sulfate, and concentrated to give an orange oil, which isdiluted with 100 mL of ether and washed with three 25-mL portions of 10%HCl. The organic layer is then dried over magnesium sulfate, filtered,and concentrated to give 1.829 g of orange solid. Column chromatographyon 100 g of silica gel (elution with 0-10% methanol in methylenechloride) gives 1.358 g of a pale orange solid. An additional columnchromatography on 150 g of silica gel (elution with 10% ether and 1%acetic acid in methylene chloride) gives 0.705 g of the title product asa yellow solid.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ11.38, 5.68, 3.02-2.93, 2.20, 1.98-1.82, 1.73-1.58,1.46-1.25, 1.24-1.08, 0.89 ppm.

¹³ C NMR (CDCl₃) δ172.3, 168.3, 165.3, 114.8, 89.7, 38.6, 36.0, 33.3,30.1, 27.2, 25.5, 22.9, 21.0, 13.9 ppm.

IR (mineral oil) 1679, 1641, 1617, 1492 cm⁻¹.

Elemental analysis, found: C, 70.90; H, 8.36.

MS (EI) m/e 236, 208, 166.

For high resolution, found: 236.1414.

EXAMPLE 1

N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-10-propyl-2H-cyclooctab!pyran-3-yl)methyl!phenyl!benzenesulfonamide (Formula A-8) Refer toChart A

A 100-mL, three-necked, round-bottomed flask with a 35-mLpressure-equalizing addition funnel filled with 3 A molecular sieves andfitted with a reflux condenser and a nitrogen inlet is charged with thetitle compound of Preparation 5 (0.196 g), p-toluenesulfonic acid (0.040g), and 30 mL of methylene chloride. The title product of Preparation 4(0.252 g) is added, and the reaction mixture is heated to reflux for 2h, then stirred at room temperature for an additional hour. The reactionmixture is then diluted with 20 mL of methylene chloride and washed with60 mL of 1:1 saturated sodium bicarbonate and brine, 30 mL of water, and30 mL of brine. The aqueous layers are combined and extracted with 30 mLof methylene chloride. The organic layers are then combined, dried overmagnesium sulfate, filtered, and concentrated to give 0.576 g of crudematerial. Column chromatography on 35 g of silica gel (elution with20-80% ether in hexane) yields 0.096 g of the title compound as a whitesolid.

Physical characteristics are as follows:

MP 87°-90° C. (decomposition).

MS (EI) m/e 521, 493, 380, 275, 262, 249, 144, 77.

For high resolution, found: 521.2236.

EXAMPLES 2-7

Following procedures analogous to those described above, the followingadditional compounds of the present invention are prepared:

2) 4-Cyano-N- 3-(R or S)-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-(R orS)-10-propyl-2H-cycloocta b!pyran-3-yl)methyl!phenyl!benzenesulfonamide

3) 4-Cyano-N- 3-(R or S)- cyclopropyl(5,6,7,8,9,10-hexahydro-(R orS)-10-cyclopropylmethyl-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!benzenesulfonamide

4) 4-Cyano-N- 3-(R or S)- cyclopropyl(5,6,7,8,9,10-hexahydro-(R orS)-10-benzyl-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!benzenesulfonamide

5) N- 3-(R or S)- cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-(Ror S)-10-propyl-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide

6) N- 3-(R or S)- cyclopropyl(5,6,7,8,9,10-hexahydro-(R orS)-10-cyclopropylmethyl-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide

7) N- 3-(R or S)- cyclopropyl(5,6,7,8,9,10-hexahydro-(R orS)-10-benzyl-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide

PREPARATION 6

(3-Benzaldehyde)-carbamic acid, phenylmethyl ester (Formula B-2) Referto Chart B

A flask with a nitrogen inlet is charged with sodium bicarbonate (10.4g) in 200 mL of THF and 200 mL of water, and m-aminobenzaldehyde offormula B-1 (10.0 g) and benzyl chloroformate (13.6 mL) are addedsequentially. The mixture is stirred at room temperature for 40 min.Ether is then added, and the organic layer is separated, washed withsaturated sodium bicarbonate, dried over sodium sulfate, filtered andconcentrated to give a brown oil. Column chromatography on 300 g ofsilica gel yields 16.3 g of the title compound as a pale yellow oil. Ananalytical sample is crystallized from ethyl acetate-hexane.

Physical characteristics are as follows:

MP 100°-104° C.

¹ H NMR (CDCl₃) δ9.98, 7.91, 7.69, 7.59, 7.43-7.35, 6.83, 5.23 ppm.

¹³ C NMR (CDCl₃) δ191.8, 153.0, 138.6, 137.1, 135.6, 129.7, 128.6,128.4, 128.3, 124.6, 124.2, 119.1, 67.2 ppm.

IR (mineral oil) 3269, 2954, 2925, 2868, 2855, 1729, 1682, 1597, 1560,1465, 1455, 1326, 1294, 1237, 1229, 1170, 1155, 1048, 695 cm-1.

Elemental analysis, found: C, 70.74; H, 5.14; N, 5.33.

MS (EI) m/e 255, 211, 91.

For high resolution, found 255.0900.

PREPARATION 7

3-(1-Hydroxy-3-methylbutyl)phenyl!-carbamic acid, phenylmethyl ester(Formula B-3 wherein R₁ is isobutyl) Refer to Chart B

A flask with a nitrogen inlet is charged with the title compound ofPreparation 6 (4.0 g) and 60 mL of dry tetrahydrofuran. The mixture iscooled to 0° C., and isobutyl magnesium chloride (17.2 mL) is added. Thereaction mixture is then allowed to warm to room temperature and stirfor 2 hours. Saturated ammonium chloride is added to quench thereaction, and the mixture is partitioned between ether and water. Theorganic layer is washed with water and concentrated to give 5.78 g ofpale yellow oil. The crude material is crystallized from ethylacetate-hexane to yield 4.13 g of the title compound as white crystals.

Physical characteristics are as follows:

MP 73°-77° C.

¹ H NMR (CDCl₃) δ7.41-7.33, 7.25, 7.05, 6.74, 5.19, 4.73-4.65, 1.91,1.73-1.65, 1.47, 0.93 ppm.

IR (Nujol) 3400, 3249, 3085, 2953, 2925, 2869, 2855, 1697, 1615, 1602,1563, 1450, 1283, 1245, 1177, 1067, 1017, 798, 773, 740, 696 cm⁻¹.

Elemental analysis, found: C, 72.58; H, 7.25; N, 4.55.

MS (El) m/z 313, 257, 213, 91.

PREPARATION 8

3- 1-(5,6,7,8,9,10-Hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)-3-methylbutyl!phenyl-carbamic acid, phenylmethyl ester(Formula B-5 wherein R₁ is isobutyl) Refer to Chart B

A 200-mL, three-necked flask with a Dien-Stark trap and a nitrogen inletis charged with p-toluenesulfonic acid (0.66 g) and toluene (100 mL) andwarmed to reflux to collect 20 mL in the Dien-Stark trap. The reactionmixture is cooled to room temperature, and the trap is emptied.4-Hydroxy-2H-cycloocta b!pyran-2-one of formula B-4 (2.48 g) and thetitle compound of Preparation 7 (4.0 g) are added to the reactionmixture and then heated to reflux for 6.5 h. The reaction mixture isallowed to stand at room temperature overnight, then poured into 350 mLof ethyl acetate, washed with two 25-mL portions of water, 25 mL ofsaturated sodium bicarbonate, and 25 mL of water. The organic layer isconcentrated to give 7.9 g of yellow oil. Column chromatography on 150 gof silica gel (elution with 10-50% ethyl acetate in hexane) gives 0.217g of the title product as an off-white foam.

Physical characteristics are as follows:

MP 73°-78° C. (decomposition).

¹ H NMR (CDCl₃) δ7.38-7.25, 7.13, 6.72, 6.01, 5.19, 4.48, 2.58, 2.41,1.93, 1.74, 1.62-1.33, 0.96 ppm.

PREPARATION 9

(R or S)- 3- 1-(5,6,7,8,9,10-Hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)-3-methylbutyl!phenyl!-carbamic acid, phenylmethyl ester(Formula B-5 wherein R₁ is isobutyl) Refer to Chart B

A stock solution of the title compound of Preparation 8 (32 mg/mL) in30% isopropyl alcohol and 0.1% acetic acid in hexane is chromatographedon a 2.0×25 cm (R, R) Whelk-O 1 column at 2 mL per injection using anautomated chromatographic system. The eluant is monitored at 310 nm, theflow rate was 10 mL/min and appropriate fractions from multipleinjections combined and concentrated in vacuo to give snowy whitesolids.

Physical characteristics are as follows:

The retention time of the title compound is 18.8 min.

PREPARATION 10

(R or S)- 3- 1-(5,6,7,8,9,10-Hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)-3-methylbutyl!phenyl!-carbamic acid, phenylmethyl ester(Formula B-5 wherein R₁ is isobutyl) Refer to Chart B

The title compound of Preparation 8 is separated as described inPreparation 9 above.

Physical characteristics are as follows:

The retention time of the title compound is 22.1 min.

PREPARATION 11

(R or S)-3-1-(3-Aminophenyl)-3-methylbutyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyranone (Formula B-6 wherein R₁ is isobutyl) Refer to Chart B

A flask with a nitrogen inlet is charged with a solution of the titlecompound of Preparation 9 (0.637 g) in 6 mL of ethanol. Cyclohexene (6mL) and 10% palladium on carbon (0.16 g) are added, and the reactionmixture is heated at reflux for 2 h. The mixture is then filteredthrough Celite and concentrated to give 0.205 g of the title compound asan off-white foam.

Physical characteristics are as follows:

MP 158°-162° C.

MS (EI) m/z 355, 312, 299, 161, 106

For high resolution, found: 355.2144.

EXAMPLE 8

(R or S)-N- 3-1-(5,6,7,8,9,10-Hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)-3-methylbutyl!phenyl!1-methyl-1H-imidazole-4-sulfonamide(Formula B-7 wherein R₁ is isobutyl and R₂ is 1-methylimidazole) Referto Chart B.

A flask with a nitrogen inlet is charged with the title compound ofPreparation 11 (0.095 g), 1-methylimidazole-4-sulfonyl chloride (0.048g), and 5 mL of methylene chloride (CH₂ Cl₂). Pyridine (0.53 mL) isadded, and the reaction mixture is stirred at room temperature for ca.18 h. A precipitate forms, which is filtered to give 0.097 g of a whitesolid. Recrystallization from methanol-chloroform yields 0.065 g of thetitle compound as a white powder.

Physical characteristics are as follows:

MP 207°-210° C.

¹ H NMR (CDCl₃) δ10.4, 10.0, 7.70, 7.11, 7.05, 6.92, 4.21, 3.64, 2.54,2.16, 1.62, 1.53, 1.43, 1.34, 0.85 ppm.

MS (EI) m/z 499, 456, 443, 306, 251, 160, 145

For high resolution, found: 499.2151

PREPARATION 12

(R or S)-3-1-(3-Aminophenyl)-3-methylbutyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyranone (Formula B-6 wherein R₁ is isobutyl) Refer to Chart B

Following the general procedure of Preparation 11, and makingnon-critical variations, but substituting the title product ofPreparation 10 for the title product of Preparation 9, 0.189 g of thetitle compound is obtained as a grey solid.

Physical characteristics are as follows:

MS (EI) m/z 355, 312, 299, 161

For high resolution, found: 355.2135

EXAMPLE 9

(R or S)-N- 3-1-(5,6,7,8,9,10-Hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)-3-methylbutyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula B-7 wherein R₁ is isobutyl and R₂ is 1-methylimidazole) Referto Chart B

Following the general procedure of Example 8, and making non-criticalvariations, but substituting the title product of Preparation 12 for thetitle product of Preparation 11, 0.047 g of the title compound isobtained as a white solid.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ10.45, 10.06, 7.70, 7.11, 7.05, 6.94, 4.21, 3.64, 2.55,2.16, 1.62, 1.53, 1.42, 1.35, 0.86 ppm.

MS (EI) m/z 499, 456, 443, 354, 306, 160, 145

For high resolution, found: 499.2146

PREPARATION 13

3-(Cyclopropyl-hydroxymethyl)-phenyl!-methanol (Formula C-2) Refer toChart C

To a solution of 6.5 mL of 3-bromobenzylalcohol of formula C-1 in 900 mLof tetrahydrofuran under nitrogen at -78° C. is added 46 mL of a 1.4Msolution of methyllithium in diethyl ether. The solution is stirred for20 min and then 66 mL of a 1.6M solution of n-butyllithium in hexane isadded. The solution is stirred 25 min and then 6 mL ofcyclopropanecarboxaldehyde is added. The solution is stirred 1.5 h,warmed to 0° C. and stirred for 40 min. Next the solution is warmed toroom temperature and stirred for 30 min. Finally the solution is heatedat reflux for 1 h. The solution is poured onto 800 mL of water andacidified with concentrated HCl followed by 5% aqueous HCl to adjust thepH to approximately 6. The layers are separated and the aqueousextracted with two portions of ethyl acetate. The combined organics aredried (Na₂ SO₄) and concentrated to afford a yellow oil which ischromatographed over 900 g 230-400 mesh silica gel (2:1 ethylacetate:hexane) to afford a 6.61 g (68%) of the desired alcohol as ayellow oil.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.41-7.26, 4.67, 3.99-3.96, 2.18, 1.28-1.14, 0.68

PREPARATION 14

3- cyclopropyl 3-hydroxymethyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one (Formula C-3) Refer to Chart C

To a solution of 501 mg of the title product of Preparation 13 in 50 mLof dichloromethane in the presence of molecular sieves 3A under nitrogenis added 492 mg of 4-hydroxy-5,6,7,8,9,10-hexahydrocyclooctab!pyran-2-one followed by 49 mg of p-toluenesulfonic acid monohydrate.The solution is heated at reflux for 2 h and then an additional 105 mgp-toluenesulfonic acid monohydrate is added and heating continued for afurther hour. The solution is concentrated in vacuo to afford a whitefoam which is treated with water and then 1N KOH and extracted with oneportion of ethyl acetate. The organic layer is washed with one portionof 1N KOH. The combined aqueous layers are acidified with 5% aqueous HCland extracted with three portions of ethyl acetate. The combinedorganics are dried (Na₂ SO₄) and concentrated in vacuo to afford ayellow oil which is chromatographed over 180 g of 230-400 mesh silicagel (2:1 ethyl acetate:hexane) to afford 436 mg of the desired benzylalcohol as a white foam.

Physical characteristics are as follows:

MP 65°-70° C.

¹ H NMR (CDCl₃) δ7.25-7.03, 4.36, 3.70-3.67, 2.41-2.37, 2.24-2.23,1.53-1.50, 1.35-1.05, 0.54-0.43, 0.42-0.21, 0.07-0.02.

PREPARATION 15

3- Cyclopropyl 3-bromomethyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one; and 3- cyclopropyl 3-chloromethyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one (Formulas C-4,5) Refer to Chart C

To a solution of 1.01 g of the title product of Preparation 14 in 70 mLof dichloromethane under nitrogen at 0° C. is added 2.00 g oftriphenylphosphine and 2.58 g of carbon tetrabromide in sequence. Thesolution is stirred 1 h and then poured onto brine. The layers areseparated and the aqueous extracted with three portions of ethylacetate. The combined organics are dried (Na₂ SO₄) and concentrated toafford a yellow oil which is triturated with ether. The solid isfiltered off and the filtrate concentrated and chromatographed over 180g of 230-400 mesh silica gel (1:1 hexane:ethyl acetate) to afford 374 mgof the desired title product as a mixture of bromide and chloride. Thesolids isolated from the filtration are chromatographed as above toafford an additional 699 mg of the title product as a mixture of bromideand chloride.

Physical characteristics are as follows:

Mass Spectrum m/e 418, 416 (M⁺ for Br), 388, 374, 372 (M⁺ for Cl), 337,246, 233, 220, 207, 195, 179, 153, 143, 129.

PREPARATION 16

3- Cyclopropyl 3-(phenylthio)methyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-Cyclooctab!pyran-2-one (Formula C-6) Refer to Chart C

To a solution of 138 mg of the title products of Preparation 15 in 5 mLof dichloromethane is added 0.04 mL of thiolphenol and 0.17 mL ofdiisopropylethylamine in sequence. The solution is heated at reflux for1 h and then allowed to stand at room temperature overnight. Thesolution is poured onto brine and treated with 5% aqueous hydrochloricacid. The layers are separated and the aqueous extracted with threeportions of ethyl acetate. The combined organics are dried (Na₂ SO₄) andconcentrated to afford a yellow oil which is chromatographed over 80 gof 230-400 mesh silica gel (2:1 hexane:ethyl acetate) to afford 111 mgof the desired sulfide as a white foam.

Physical characteristics are as follows:

MP 137°-139° C.

Mass Spectrum m/e 446 (M⁺), 418, 337, 295, 233, 220, 207, 185, 145, 128,109, 91, 79, 55, 40.

EXAMPLE 10

3- Cyclopropyl 3-(phenylsulfonyl)methyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-Cyclooctab!pyran-2-one (Formula C-7) Refer to Chart C

To a solution of 119 mg of the title product of Preparation 16 in 5 mLof tetrahydrofuran and 5 mL of methanol at 0° C. is added a solution of279 mg of oxone in 5 mL of water. The solution is stirred 2.5 h and thenwarmed to room temperature and stirred 2 h. The solution is filtered andthe solids washed with chloroform. The filtrate is diluted with waterand the layers are separated. The aqueous is extracted with threeportions of ethyl acetate. The combined organics are dried (Na₂ SO₄) andconcentrated to afford a clear oil which is chromatographed over 80 g of230-400 mesh silica gel (1:1 hexane:ethyl acetate) to afford 78 mg ofthe title product as a white foam.

Physical characteristics are as follows:

MP 80°-85° C.

Mass Spectrum m/e 479 (M⁺ +1), 463, 450, 391, 337, 309, 207, 161, 149,127, 115, 71, 57, 41.

Exact mass found: 479.1885.

EXAMPLES 11-39

The following compounds of the present invention are prepared by ananalogous synthetic route to that described above:

11) 3- cyclopropyl 3-(4-cyanophenylsulfonyl)methyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one

The starting material, 4-cyanobenzenethiol, is prepared from4-cyanobenzenesulfonyl chloride according to a general literatureprocedure: Wagner, A. W. Ber Deutsch Chem Ges, 99:375 (1966).

Physical characteristics are as follows:

MP 100°-105° C.

Mass Spectrum m/e 504 (M⁺ +1), 337, 247, 207, 143.

Exact mass found 504.1843.

12) 3- cyclopropyl 3-(4-fluorophenylsulfonyl)methyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one

Physical characteristics are as follows:

MP 95°-100° C.

¹ H NMR (CDCl₃) δ7.61-7.57, 7.40-7.37, 7.27-7.20, 7.13-7.07, 7.02-6.99,6.42, 4.30, 3.88-3.85, 2.64-2.61, 2.51-2.47, 1.83-1.40, 1.40-1.27,0.69-0.58, 0.48-0.43, 0.19-0.14.

13) 3- cyclopropyl 3-(4-methylphenylsulfonyl)methyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one

Physical characteristics are as follows:

MP 100°-105° C.

¹ H NMR (CDCl₃) δ7.37-7.34, 7.25-7.22, 7.17-7.05, 6.86-6.84, 4.15,3.60-3.58, 2.52-2.42, 2.42-2.30, 2.28, 1.70-1.14, 0.57-0.32, 0.32-0.20,0.06-(-)0.16.

14) 3- cyclopropyl 3-(4-carboxyphenylsulfonyl)methyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one

Physical characteristics are as follows:

MP 90°-95° C.

Mass Spectrum m/e 523 (M⁺ +1), 337, 247, 207, 143.

Exact mass found 523.1785.

15) 3- cyclopropyl 3-(2-(1-methylimidazoyl)sulfonyl)methyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one

Physical characteristics are as follows:

MP 95°-103° C.

¹ H NMR (CDCl₃) δ7.36-7.34, 7.29-7.27, 7.14, 7.06-7.03, 6.98 (s, 1H),6.86, 4.30, 3.73-3.70, 3.20, 2.67-2.54, 1.90-1.36, 0.71-0.50, 0.46-0.33,0.18-0.03.

16) 3- cyclopropyl 3-(2-pyrimidinylsulfonyl)methyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one

17) 3- cyclopropyl 3-(2-pyridinylsulfonyl)methyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one

18) 3- cyclopropyl 3-(1-methyl-4-imidazolylsulfonyl)methyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one

19) 3- cyclopropyl 3-(5-cyano-2-pyridinylsulfonyl)methyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one

20) 3- cyclopropyl 3-(2-benzimidazolylsulfonyl)methyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one

21) 3- cyclopropyl 3-(2-quinolinylsulfonyl)methyl!phenyl!methyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one

22) 3- cyclopropyl 3-(4-cyanophenylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-coumarin

23) 3- cyclopropyl 3-(2-pyridinylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-coumarin

24) 3- cyclopropyl 3-(1-methyl-4-imidazolylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-coumarin

25) 3- cyclopropyl 3-(5-cyano-2-pyridinylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-coumarin

26) 3- cyclopropyl 3-(2-benzimidazolylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-coumarin

27) 3- cyclopropyl 3-(2-quinolinylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-coumarin

28) 3- cyclopropyl 3-(4-cyanophenylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-6-1-(phenylmethyl)propyl!-2H-pyran-2-one

29) 3- cyclopropyl 3-(2-pyridinylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-6-1-(phenylmethyl)propyl!-2H-pyran-2-one

30) 3- cyclopropyl 3-(1-methyl-4-imidazolylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-6-1-(phenylmethyl)propyl!-2H-pyran-2-one

31) 3- cyclopropyl 3-(5-cyano-2-pyridinylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-6-1-(phenylmethyl)propyl!-2H-pyran-2-one

32) 3- cyclopropyl 3-(2-benzimidazolylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-6-1-(phenylmethyl)propyl!-2H-pyran-2-one

33) 3- cyclopropyl 3-(2-quinolinylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-6-1-(phenylmethyl)propyl!-2H-pyran-2-one

34) 3- cyclopropyl 3-(4-cyanophenylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro-2H-pyran-2-one

35) 3- cyclopropyl 3-(2-pyridinylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro-2H-pyran-2-one

36) 3- cyclopropyl 3-(1-methyl-4-imidazolylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro-2H-pyran-2-one

37) 3- cyclopropyl 3-(5-cyano-2-pyridinylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro-2H-pyran-2-one

38) 3- cyclopropyl 3-(2-benzimidazolylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro-2H-pyran-2-one

39) 3- cyclopropyl 3-(2-quinolinylsulfonyl)methyl!phenyl!methyl!-4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro-2H-pyran-2-one

PREPARATION 17

5,6-Dihydro-4-Hydroxy-6-phenethyl-6-propyl-2H-pyran-2-one (Formula D-1:R₁ is phenethyl, R₂ is propyl) Refer to Chart D

Methyl acetoacetate (1.47 mL) is added to a suspension of sodium hydride(567 mg, 60% dispersion in mineral oil) in THF (30 mL) at 0° C. After 15minutes, n-butyl lithium (8.5 mL, 1.6M solution in hexane) is addeddropwise and the reaction is stirred 15 minutes. 1-Phenyl-3-hexanone(2.0 g) is then added via syringe all at once to the reaction mixture.The reaction is stirred an additional hour, then poured into a saturatedammonium chloride solution. It is extracted with EtOAc, dried overanhydrous sodium sulfate and evaporated in vacuo. The material obtainedis dissolved in THF (25 mL) and a 0.1N sodium hydroxide (113 mL)solution is added. After stirring three hours, the mixture is extractedwith ethyl acetate (1×). The aqueous layer is adjusted to pH 3 withhydrochloric acid, then extracted with CH₂ Cl₂ (3×25 mL), dried overanhydrous magnesium sulfate and evaporated to afford the title productas a white solid.

Physical characteristics are as follows:

¹ H NMR (300 MHz, CDCl₃): δ0.96, 1.21, 1.48, 1.72, 1.98, 2.73, 3.43,7.15-7.32.

Anal. Found: C, 73.77; H, 7.96.

PREPARATION 18

4-Hydroxy-3-1-(3-nitrophenyl)-propyl!-5,6-dihydro-6-phenethyl-6-propyl-2H-pyran-2-one(Formula D-4: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl) Refer to ChartD

To a solution of the title product of Preparation 17 (Formula D-1: R₁ isphenethyl, R₂ is propyl) (1 g) and 3-nitrobenzaldehyde (Formula D-2)(581 mg) in dry THF at 0° C. is added AlCl₃ (1.0 g) as one solidportion. The cooling bath is removed and the yellow solution is allowedto stir at room temperature for 2 hrs. The reaction mixture is quenchedby the addition of solid Na₂ CO₃ -10H₂ O (2.2 g) and vigorously stirredfor 5 min. The mixture is filtered through celite with ether and thefiltrate is evaporated to dryness in vacuo. The benzylidene intermediateof the formula D-3 and CuBr--Me₂ S (237 mg) are dissolved in dry THF anda solution of Et₃ Al (4.23 mL; 1M in hexane) is added at roomtemperature, dropwise over 5 min. When the reaction is complete (asdetermined by tlc), it is quenched by the addition of water and thereaction mixture is transferred to a separatory funnel with ether. Theaqueous layer is extracted with ether (3×15 mL) and the combined organiclayers are washed with brine, dried (MgSO₄), filtered and evaporated invacuo to provide an oil. Flash chromatography on silica gel withHexanes/EtOAc (3:1) provides 1.1 g of the title product as a lightyellow foam.

Physical characteristics are as follows:

¹ H NMR complicated by presence of diastereomers.

¹ H NMR (300 MHz, CD₃ OD) δ0.93, 1.37, 1.74, 1.82-2.14, 2.29, 2.52-2.71,4.19, 6.98-7.24, 7.44, 7.72, 8.02, 8.26.

PREPARATION 19

3-Cyclopropyl-(3-nitrophenyl)-methyl!-4-hydroxy-5,6-dihydro-6-phenethyl-6-propyl-2H-pyran-2-one(Formula D-4: R₁ is phenethyl, R₂ is propyl, R₃ is cyclopropyl) Refer toChart D

To a solution of the title product of Preparation 17 (Formula D-1: R₁ isphenethyl, R₂ is propyl) (1 g) and 3-nitrobenzaldehyde (Formula D-2)(581 mg) in dry THF at 0° C. is added AlCl₃ (1.0 g) as one solidportion. The cooling bath is removed and the yellow solution is allowedto stir at room temperature for 2 hrs. The reaction mixture is quenchedby the addition of solid Na₂ CO₃ -10H₂ O (2.2 g) and vigorously stirredfor 5 min. The mixture is filtered through celite with ether and thefiltrate is evaporated to dryness in vacuo. The benzylidene intermediateof formula D-3 and CuBr--Me₂ S (237 mg) are dissolved in dry THF andcooled to -78° C. A solution of cyclopropylmagnesium bromide (15.6 mL;0.25M in THF) is added dropwise over 10 min and the reaction mixture isstirred for 30 min. The reaction is quenched by the addition of waterand neutralized by the addition of 1N HCl. The reaction mixture istransferred to a separatory funnel with ether and the aqueous layer isextracted with ether (3×15 mL). The combined organic layers are washedwith brine, dried (MgSO₄), filtered and evaporated in vacuo to providean oil. Flash chromatography on silica gel with Hexanes/EtOAc (3:1)provides 0.9 g of the title product as a light yellow foam.

Physical characteristics are as follows:

¹ H NMR complicated by presence of diastereomers.

¹ H NMR (300 MHz, CD₃ OD) δ0.25, 0.53, 0.74, 0.94, 1.41, 1.68-2.13,2.57-2.72, 3.38, 7.04-7.23, 7.46, 7.82, 8.03, 8.30.

PREPARATION 20

3-1-(3-Aminophenyl)-propyl!-4-hydroxy-5,6-dihydro-6-phenethyl-6-propyl-2H-pyran-2-one(Formula D-5: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl) Refer to ChartD

To a solution of the title product of Preparation 18 (Formula D-4: R₁ isphenethyl, R₂ is propyl, R₃ is ethyl) (350 mg) in MeOH at roomtemperature is added 10% Pd/C (35 mg) and ammonium formate (521 mg). Theresulting mixture is stirred for 2 hrs. and then filtered through celitewith CH₂ Cl₂. The filtrate is evaporated in vacuo and the residue istriturated with CH₂ Cl₂ (3×10 mL). The combined organic solution isfiltered and evaporated in vacuo to provide the 325 mg of the titlecompound as a light yellow foam.

Physical characteristics are as follows:

¹ H NMR complicated by presence of diastereomers.

¹ H NMR (300 MHz, CDCl₃) δ0.89, 1.40, 1.64-2.07, 2.20, 2.62, 3.94, 6.54,6.72-7.25.

The compounds of formula D-5, wherein R₁ is propyl, R₂ is propyl and R₃is ethyl or t-butyl are prepared by analogous procedures.

Physical characteristics of the compound of the formula D-5, wherein R₁is and R₂ are propyl and R₃ is ethyl, are as follows:

¹ H NMR: 0.9, 1.3, 1.5-1.8, 2.0, 2.2, 2.5, 3.9, 4.5, 6.5, 6.8, 7.0 ppm

TLC R_(f) : 0.32 (10% ethyl acetate in dichloromethane).

EXAMPLE 40

4-Cyano-N- 3-1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-benzenesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is4-cyanophenyl) Refer to Chart D

To a solution of the title product of Preparation 20 (Formula D-5: R₁ isphenethyl, R₂ is propyl, R₃ is ethyl) (30 mg) and 4-cyanobenzenesulfonylchloride of formula D-7, wherein R₄ is cyanophenyl, (16.1 mg) in CH₂ Cl₂(1 mL) at room temperature is added pyridine (13 μL) via syringe. Theresulting solution is stirred for 3 hrs, after which the starting amineis consumed. The mixture is flash chromatographed on silica gel with the5% EtOAc in CH₂ Cl₂ to provide 21 mg of the title product as a whitefoam.

Physical characteristics are as follows:

¹ H NMR complicated by presence of diastereomers.

¹ H NMR (300 MHz, CDCl₃) δ0.6-1.1, 1.2-2.2, 2.4-2.7, 3.86-4.01,6.89-7.45, 7.66-7.92.

HRMS found: 559.2267.

EXAMPLE 41

N- 3-1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is1-methylimidazol-4-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5; R₁ is phenethyl, R₂ is propyl, R₃ is ethyl) and1-methyl-imidazole-4-sulfonyl chloride of formula D-7 wherein R₄ is1-methylimidazol-4-yl, using the general procedure for sulfonylation ofExample 40 to yield the title compound as an off-white amorphous solidafter flash chromatography with 4% MeOH/EtOAc.

Physical characteristics are as follows:

¹ H NMR complicated by presence of diastereomers and tautomerism.

¹ H NMR (300 MHz, CDCl₃) δ0.75-0.96, 1.17-1.43, 1.45-2.11, 2.43-2.68,3.24, 3.64, 3.94, 6.72-7.51.

HRMS found: 538.2383.

EXAMPLE 42

N- 3-1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-8-quinolinesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ isquinolin-8-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl) and 8-quinolinesulfonylchloride of formula D-7 wherein 4₄ is quinolin-8-yl, using the generalprocedure for sulfonylation of Example 40 to yield the title compound asa white amorphous solid after flash chromatography with 5% EtOAc/CH₂Cl₂.

Physical characteristics are as follows:

¹ H NMR complicated by presence of diastereomers and tautomerism.

¹ H NMR (300 MHz, CDCl₃) δ0.66, 0.90, 1.17-1.44, 1.58-2.03, 2.38-2.64,3.77, 6.68-7.27, 7.35-7.69, 8.02, 8.26, 9.14.

HRMS found: 585.2402.

EXAMPLE 43

N- 3-1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-8-quinolinesulfonamide(Formula D-6: R₁ is R₂ is propyl, R₃ is ethyl, R₄ is quinolin-8-yl)Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is propyl, R₂ is propyl, R₃ is ethyl) and 8-quinolinesulfonylchloride of formula D-7 wherein R₄ is quinolin-8-yl, using the generalprocedure for sulfonylation of Example 40 to yield the title compound asa white amorphous solid after flash chromatography with 5% EtOAc/CH₂Cl₂.

Physical characteristics are as follows:

¹ H NMR complicated by presence of diastereomers and tautomerism.

¹ H NMR (300 MHz, CD₃ OD) δ0.67, 0.85, 1.27, 1.54, 2.01, 3.73, 6.78,6.90, 7.04, 7.57, 8.12, 8.29, 8.38, 9.13.

HRMS found: 523.2276.

Anal. found: C, 66.09; H, 6.60; N, 5.13.

EXAMPLE 44

N- 3-1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1-methyl-1H-imidazolesulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is ethyl, R₄ is1-methylimidazol-4-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is propyl, R₂ is propyl, R₃ is ethyl) and1-methyl-imidazole-4-sulfonyl chloride of formula D-7 wherein R₄ is1-methylimidazol-4-yl, using the general procedure for sulfonylation ofExample 40 to yield the title compound as an off-white amorphous solidafter flash chromatography with 4% MeOH/EtOAc.

Physical characteristics are as follows:

¹ H NMR (300 MHz, CD₃ OD) δ0.88, 1.32, 1.64, 1.93, 2.16, 2.56, 3.68,3.91, 6.87, 7.03, 7.14, 7.53, 7.64.

HRMS found: 476.2223.

EXAMPLE 45

4-Fluoro-N- 3-1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-benzenesulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is ethyl, R₄ is4-fluorophenyl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is propyl, R₂ is propyl, R₃ is ethyl) and4-fluoro-benzenesulfonyl chloride of formula D-7 wherein R₄ is4-fluorophenyl, using the general procedure for sulfonylation of Example40 to yield the title compound as a white amorphous solid after flashchromatography with 5% EtOAc/CH₂ Cl₂.

Physical characteristics are as follows:

¹ H NMR complicated by presence of diastereomers and tautomerism.

¹ H NMR (300 MHz, CDCL₃) δ0.51-1.03, 1.15-1.73, 1.81-2.48, 2.73, 3.91,6.69, 6.88, 7.09, 7.78.

HRMS found: 490.2085.

EXAMPLE 46

4-Cyano-N- 3-1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-benzenesulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is ethyl, R₄ is4-cyanophenyl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is propyl, R₂ is propyl, R₃ is ethyl) and4-cyano-benzenesulfonyl chloride of formula D-7 wherein R₄ is4-cyanophenyl, using the general procedure for sulfonylation of Example40 to yield the title compound as a white amorphous solid after flashchromatography with 5% EtOAc/CH₂ Cl₂.

Physical characteristics are as follows:

¹ H NMR complicated by presence of diastereomers and tautomerism.

¹ H NMR (300 MHz, CDCl₃) δ0.68-0.96, 1.15-1.42, 1.44-1.76, 1.83-2.12,3.18, 3.88, 6.69-7.18, 7.71, 7.85.

HRMS found: 497.2126.

EXAMPLE 47

N- 3-1-(4-hydroxy-6,6-diisobutyl-2-oxo-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is isobutyl, R₂ is isobutyl, R₃ is ethyl, R₄ is1-methylimidazol-4-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is propyl, R₂ is isobutyl, R₃ is ethyl) and1-methyl-imidazole-4-sulfonyl chloride of formula D-7 wherein R₄ is1-methylimidazol-4-yl, using the general procedure for sulfonylation ofExample 40 to yield the title compound as an off-white amorphous solidafter flash chromatography with 4% MeOH/EtOAc.

Physical characteristics are as follows:

¹ H NMR (300 MHz, CD₃ OD) δ0.82-0.94, 1.52-1.83, 1.86-2.03, 2.06-2.22,2.60, 3.68, 3.92, 6.87, 7.03, 7.16, 7.56, 7.65.

HRMS found: 504.2531.

Anal. found: C, 62.03; H, 7.43; N, 8.20.

EXAMPLE 48

N- 3-1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-pyran-3-yl)-cyclopropylmethyl!-phenyl!-1-methyl-1H-imidazolesulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is cyclopropyl, R₄ is1-methylimidazol-4-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is propyl, R₂ is propyl, R₃ is cyclopropyl) and1-methyl-imidazole-4-sulfonyl chloride of formula D-7 wherein R₄ is1-methylimidazol-4-yl, using the general procedure for sulfonylation ofExample 40 to yield the title compound as an off-white amorphous solidafter flash chromatography with 4% MeOH/EtOAc.

Physical characteristics are as follows:

¹ H NMR (300 MHz, CD₃ OD) δ0.12, 0.43, 0.68, 0.90-0.97, 1.36, 1.71,2.60, 3.12, 3.67, 6.88, 7.06, 7.24, 7.51, 7.65.

HRMS found: 488.2225.

Anal. found: C, 61.25; H, 6.94; N, 8.42.

EXAMPLE 49

N- 3-1-(4-Hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-pyran-3-yl)-cyclopropylmethyl!-phenyl!-8-quinolinesulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is cyclopropyl, R₄ isquinolin-8-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is propyl, R₂ is propyl, R₃ is cyclopropyl) and8-quinolinesulfonyl chloride of formula D-7 wherein R₄ is quinolin-8-yl,using the general procedure for sulfonylation of Example 40 to yield thetitle compound as a white amorphous solid after flash chromatographywith 5% EtOAc/CH₂ Cl₂.

Physical characteristics are as follows:

¹ H NMR (300 MHz, CD₃ OD) δ-0.14, 0.01, 0.35, 0.89, 1.35, 1.63, 2.52,2.94, 6.79, 6.94, 7.09, 7.64, 8.12, 8.28, 8.41, 9.13.

HRMS found: 535.2256

Anal. found: C, 67.58; H, 6.53; N, 5.11.

EXAMPLE 50

4-Cyano-N- 3-1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-pyran-3-yl)-cyclopropylmethyl!-phenyl!-benzenesulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is cyclopropyl, R₄ is4-cyanophenyl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is propyl, R₂ is propyl, R₃ is cyclopropyl) and4-cyano-benzenesulfonyl chloride of formula D-7 wherein R₄ is4-cyanophenyl, using the general procedure for sulfonylation of Example40 to yield the title compound as a white amorphous solid after flashchromatography with 5% EtOAc/CH₂ Cl₂.

Physical characteristics are as follows:

¹ H NMR (300 MHz, CD₃ OD) δ0.13, 0.44, 0.62, 0.91, 1.19, 1.67, 2.57,3.14, 6.80, 7.12, 7.25, 7.83.

HRMS found: 509.2096

Anal. found: C, 65.86; H, 6.39; N, 5.48.

EXAMPLE 51

4-Fluoro-N- 3-1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-pyran-3-yl)-cyclopropylmethyl!-phenyl!-benzenesulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is cyclopropyl, R₄ is4-fluorophenyl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is propyl, R₂ is propyl, R₃ is cyclopropyl) and4-fluoro-benzenesulfonyl chloride of formula D-7 wherein R₄ is4-fluorophenyl, using the general procedure for sulfonylation of Example40 to yield the title compound as a white amorphous solid after flashchromatography with 5% EtOAc/CH₂ Cl₂.

Physical characteristics are as follows:

¹ H NMR (300 MHz, CD₃ OD) δ0.11, 0.43, 0.62, 0.92, 1.34, 1.65, 2.57,3.13, 6.79, 7.03-7.24, 7.75.

HRMS found: 502.2063.

Anal. found: C, 63.96; H, 6.29; N, 2.71.

PREPARATION 21

Chiral HPLC resolution of 4-Hydroxy-3-1-(3-nitrophenyl)-propyl!-5,6-dihydro-6,6-dipropyl-2H-pyran-2-one(Formula D-4: R₁ is propyl, R₂ is propyl, R₃ is ethyl) Refer to Chart D

A solution of the title product of Preparation 18 (Formula D-4: R₁ ispropyl, R₂ is propyl, R₃ is ethyl) (30 mg/mL) in 15% isopropyl alcoholin hexane is chromatographed on a 2.0×25 cm (R,R) Whelk-O 1 (Registechnologies, Inc., Morton Grove, Ill. 60053) column at 1 mL perinjection using an automated chromatographic system. The eluant ismonitored at 270 nM and appropriate fractions from multiple injectionscombined and concentrated in vacuo to give tan oils. Fractions frommultiple injections are analyzed on a 0.46×25 cm (S,S) Whelk-O 1 columnwith the same solvent at 1.0 mL/min. The first peak from the 1.0 cmcolumn is >99% ee (Rt is min) and the latter peak is 92% ee (Rt is min).Prior to further use, the resolved materials are subjected to flashchromatography on silica gel with 3:1 hexanes/EtOAc. The resolvedmaterials are converted to the amines of Formula D-5 using theconditions described in Preparation 20.

Physical characteristics are as follows:

The resolved materials were found to exhibit identical ¹ H NMR and tlcbehavior as the racemic material.

EXAMPLE 52

(R or S)-N- 3-1-(4-Hydroxy-2-oxo-6,6-dipropyl-6,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-8-quinolinesulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is ethyl, R₄ isquinolin-8-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 21 (FormulaD-5: R₁ is propyl, R₂ is propyl, R₃ is ethyl) and 8-quinolinesulfonylchloride of formula D-7 wherein R₄ is quinolin-8-yl, using the generalprocedure for sulfonylation of Example 40 to yield the title compound asa white amorphous solid after flash chromatography with 5% EtOAc/CH₂Cl₂.

Physical characteristics are as follows:

¹ H NMR and tlc behavior is identical to that of racemic mixture.

¹ H NMR (300 MHz, CD₃ OD) δ0.67, 0.85, 1.27, 1.54, 2.01, 3.73, 6.78,6.90, 7.04, 7.57, 8.12, 8.29, 8.38, 9.13.

MS m/e (rel%): 523 (100), 524 (34), 129 (11), 525 (11), 522 (10), 130(7), 139 (5), 134 (4).

EXAMPLE 53

(R or S)-N- 3-1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is ethyl, R₄ is1-methylimidazol-4-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 21 (FormulaD-5: R₁ is propyl, R₂ is propyl, R₃ is ethyl) and1-methyl-imidazole-4-sulfonyl chloride of formula D-7 wherein R₄ is1-methylimidazol-4-yl, using the general procedure for sulfonylation ofExample 40 to yield the title compound as an off-white amorphous solidafter flash chromatography with 4% MeOH/EtOAc.

Physical characteristics are as follows:

¹ H NMR and tlc behavior is identical to racemic mixture.

¹ H NMR (300 MHz, CD₃ OD) δ0.88, 1.32, 1.64, 1.93, 2.16, 2.56, 3.68,3.91, 6.87, 7.03, 7.14, 7.53, 7.64.

MS m/e (rel%): 476 (100), 477 (28), 139 (14), 492 (12), 134 (11), 278(10), 478 (10), 83 (9), 552 (8), 145 (7).

EXAMPLE 54

(S or R)-N- 3-1-(4-Hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-8-quinolinesulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is ethyl, R₄ isquinolin-8-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 21 (FormulaD-5: R₁ is propyl, R₂ is propyl, R₃ is ethyl) and 8-quinolinesulfonylchloride of formula D-7 wherein R₄ is quinolin-8-yl, using the generalprocedure for sulfonylation of Example 40 to yield the title compound asa white amorphous solid after flash chromatography with 5% EtOAc/CH₂Cl₂.

Physical characteristics are as follows:

¹ H NMR and tlc behavior is identical to that of racemic mixture.

¹ H NMR (300 MHz, CD₃ OD) δ0.67, 0.85, 1.27, 1.54, 2.01, 3.73, 6.78,6.90, 7.04, 7.57, 8.12, 8.29, 8.38, 9.13.

MS m/e (rel%): 523 (100), 524 (34), 522 (24), 539 (13), 525 (10), 129(10), 130 (5), 134 (5), 128 (5), 540 (5).

EXAMPLE 55

(S or R)-N- 3-1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is ethyl, R₄ is1-methylimidazol-4-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 21 (FormulaD-5: R₁ is propyl, R₂ is propyl, R₃ is ethyl) and1-methyl-imidazole-4-sulfonyl chloride of formula D-7 wherein R₄ is1-methylimidazol-4-yl, using the general procedure for sulfonylation ofExample 40 to yield the title compound as an off-white amorphous solidafter flash chromatography with 4% MeOH/EtOAc.

Physical characteristics are as follows:

¹ H NMR and tlc behavior is identical to racemic mixture.

¹ H NMR (300 MHz, CD₃ OD) δ0.88, 1.32, 1.64, 1.93, 2.16, 2.56, 3.68,3.91, 6.87, 7.03, 7.14, 7.53, 7.64.

MS m/e (rel%): 476 (100), 477 (28), 139 (19), 490 (15), 498 (14), 83(12), 478 (9), 55 (9), 145 (9), 134 (7).

EXAMPLE 56

(R or S)-N- 3-1-(4-Hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-pyran-3-yl)-cyclopropylmethyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is cyclopropyl, R₄ is1-methylimidazol-4-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 21 (FormulaD-5: R₁ is propyl, R₂ is propyl, R₃ is cyclopropyl) and1-methyl-imidazole-4-sulfonyl chloride of formula D-7 wherein R₄ is1-methylimidazol-4-yl, using the general procedure for sulfonylation ofExample 40 to yield the title compound as an off-white amorphous solidafter flash chromatography with 4% MeOH/EtOAc.

Physical characteristics are as follows:

¹ H NMR and tlc behavior is identical to racemic mixture.

¹ H NMR (300 MHz, CD₃ OD) δ0.12, 0.43, 0.68, 0.90-0.97, 1.36, 1.71,2.60, 3.12, 3.67, 6.88, 7.06, 7.24, 7.51, 7.65.

MS m/e (rel%): 488 (100), 489 (30), 139 (18), 145 (14), 490 (10), 55(10), 83 (9), 564 (7), 146 (7), 510 (7).

EXAMPLE 57

(S or R)-N- 3-1-(4-Hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-pyran-3-yl)-cyclopropylmethyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is cyclopropyl, R₄ is1-methylimidazol-4-yl) Refer to Chart D

The title compound is prepared from the amine Preparation 21 (FormulaD-5: R₁ is propyl, R₂ is propyl, R₃ is cyclopropyl) and1-methyl-imidazole-4-sulfonyl chloride of formula D-7 wherein R₄ is1-methylimidazol-4-yl, using the general procedure for sulfonylation ofExample 40 to yield the title compound as an off-white amorphous solidafter flash chromatography with 4% MeOH/EtOAc.

Physical characteristics are as follows:

¹ H NMR and tlc behavior is identical to racemic mixture.

¹ H NMR (300 MHz, CD₃ OD) δ0.12, 0.43, 0.68, 0.90-0.97, 1.36, 1.71,2.60, 3.12, 3.67, 6.88, 7.06, 7.24, 7.51, 7.65.

MS m/e (rel%): 488 (100), 489 (29), 139 (18), 145 (16), 83 (10), 55(10), 490 (10), 510 (8), 146 (8), 144 (7).

EXAMPLE 58

4-Cyano-N- 3-1-(4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-cyclopropylmethyl!-phenyl!-benzenesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is cyclopropyl, R₄ is4-cyanophenyl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is phenethyl, R₂ is propyl, R₃ is cyclopropyl) and4-fluoro-benzenesulfonyl chloride of formula D-7 wherein R₄ is4-cyanophenyl, using the general procedure for sulfonylation of Example40 to yield the title compound as a white amorphous solid after flashchromatography with 5% EtOAc/CH₂ Cl₂.

Physical characteristics are as follows:

¹ H NMR (300 MHz, CD₃ OD) δ0.11, 0.42, 0.61, 0.95, 1.24, 1.74-2.00,2.61-2.73, 3.30, 6.83-7.23, 7.71-7.84.

HRMS found: 571.2267

EXAMPLE 59

4-Fluoro-N- 3-1-(4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-cyclopropylmethyl!-phenyl!-benzenesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is cyclopropyl, R₄ is4-fluorophenyl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is phenethyl, R₂ is propyl, R₃ is cyclopropyl) and4-fluoro-benzenesulfonyl chloride of formula D-7 wherein R₄ is4-fluorophenyl, using the general procedure for sulfonylation of Example40 to yield the title compound as a white amorphous solid after flashchromatography with 5% EtOAc/CH₂ Cl₂.

Physical characteristics are as follows:

¹ H NMR complicated by presence of diastereomers.

¹ H NMR (300 MHz, CD₃ OD) δ0.11, 0.43, 0.67, 0.96, 1.41, 1.67-2.13,2.62, 3.16, 6.84, 7.02-7.31, 7.72.

HRMS found: 564.2211.

EXAMPLE 60

N- 3-1-(4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-cyclopropylmethyl!-phenyl!-8-quinolinesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is cyclopropyl, R₄ isquinolin-8-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is phenethyl, R₂ is propyl, R₃ is cyclopropyl) and8-quinolinesulfonyl chloride of formula D-7 wherein R₄ is quinolin-8-yl,using the general procedure for sulfonylation of Example 40 to yield thetitle compound as a white amorphous solid after flash chromatographywith 5% EtOAc/CH₂ Cl₂.

Physical characteristics are as follows:

¹ H NMR complicated by presence of diastereomers.

¹ H NMR (300 MHz, CD₃ OD) δ-0.13, 0.01, 0.35, 0.93, 1.46, 1.54,1.58-2.06, 2.56, 2.96, 6.81-7.23, 7.50-7.68, 8.08, 8.24, 8.37, 9.12.

HRMS found: 597.2398

EXAMPLE 61

N- 3-1-(4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-cyclopropylmethyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is cyclopropyl, R₄ is1-methyl-imidazol-4-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is phenethyl, R₂ is propyl, R₃ is cyclopropyl) and1-methyl-imidazole-4-sulfonyl chloride of formula D-7 wherein R₄ is1-methylimidazol-4-yl using the general procedure for sulfonylation ofExample 40 to yield the title compound as a white amorphous solid afterflash chromatography with 5% EtOAc/CH₂ Cl₂.

Physical characteristics are as follows:

¹ H NMR complicated by presence of diastereomers.

¹ H NMR (300 MHz, CD₃ OD) δ0.13, 0.42, 0.67, 0.95, 1.44, 1.68-2.13,2.56, 3.17, 6.91, 7.01-7.33, 7.52, 7.63.

HRMS found: 550.2370.

EXAMPLE 62

N- 3-1-(4-Hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-cyclopropylmethyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is phenethyl, R₃ is cyclopropyl, R₄ is1-methyl-imidazol-4-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is phenethyl, R₂ is phenethyl, R₃ is cyclopropyl) and1-methyl-imidazole-4-sulfonyl chloride of formula D-7 wherein R₄ is1-methylimidazol-4-yl, using the general procedure for sulfonylation ofExample 40 to yield the title compound as a white amorphous solid afterflash chromatography with 5% EtOAc/CH₂ Cl₂.

Physical characteristics are as follows:

¹ H NMR (300 MHz, CD₃ OD) δ0.13, 0.42, 0.68, 1.73, 1.88-2.17, 2.68,3.19, 3.64, 6.93, 7.02-7.31, 7.52, 7.64.

HRMS found: 612.2530.

EXAMPLE 63

N- 3-1-(4-Hydroxy-2-oxo-6,6-dipentyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is pentyl, R₂ is pentyl, R₃ is ethyl, R₄ is1-methyl-imidazol-4-yl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is pentyl, R₂ is pentyl, R₃ is ethyl) and1-methyl-imidazole-4-sulfonyl chloride of formula D-7 wherein R₄ is1-methylimidazole-4-yl, using the general procedure for sulfonylation ofExample 40 to yield the title compound as a white amorphous solid afterflash chromatography with 5% EtOAc/CH₂ Cl₂.

Physical characteristics are as follows:

¹ H NMR (300 MHz, CD₃ OD) δ0.87, 1.25, 1.55-1.68, 1.92, 2.13, 2.57,3.66, 3.93, 6.86, 7.03, 7.16, 7.55, 7.63.

EXAMPLE 64

4-Cyano-N- 3-1-(4-Hydroxy-2-oxo-6,6-dipentyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-benzenesulfonamide(Formula D-6: R₁ is pentyl, R₂ is pentyl, R₃ is ethyl, R₄ is4-cyanophenyl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is pentyl, R₂ is pentyl, R₃ is ethyl) and1-methyl-imidazole-4-sulfonyl chloride of formula D-7 wherein R₄ is4-cyanophenyl, using the general procedure for sulfonylation of Example40 to yield the title compound as a white amorphous solid after flashchromatography with 5% EtOAc/CH₂ Cl₂.

Physical characteristics are as follows:

¹ H NMR (300 MHz, CD₃ OD) δ0.86, 1.23, 1.52-1.67, 1.93, 2.14, 2.56,3.93, 6.80, 7.05, 7.18, 7.80, 7.86.

EXAMPLES 65-93

Using the general procedure of Example 40, but substituting theappropriate reactants, the following compounds of the present inventionare prepared:

EXAMPLE 65

N- 3- 1(R or S)-(6(R orS)-4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is1-methylimidazol-4-yl) Refer to Chart D

EXAMPLE 66

N- 3- 1(R or S)-(6(S orR)-4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is1-methylimidazol-4-yl) Refer to Chart D

EXAMPLE 67

N- 3- 1(S or R)-(6(R orS)-4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is1-methylimidazol-4-yl) Refer to Chart D

EXAMPLE 68

N- 3- 1(S or R)-(6(S orR)-4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is1-methylimidazol-4-yl) Refer to Chart D

EXAMPLE 69

N- 3-t-Butyl-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-methyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is t-butyl, R₄ is1-methylimidazol-4-yl) Refer to Chart D

EXAMPLE 70

4-Cyano-N- 3-t-butyl-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-methyl!-phenyl!-benzenesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is t-butyl, R₄ is4-cyanophenyl) Refer to Chart D

EXAMPLE 71

4-Fluoro-N- 3-t-butyl-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-methyl!-phenyl!-benzenesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is t-butyl, R₄ is4-fluorophenyl) Refer to Chart D

EXAMPLE 72

N- 3-t-Butyl-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-methyl!-phenyl!-8-quinolinesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is t-butyl, R₄ isquinolin-8-yl) Refer to Chart D

EXAMPLE 73

N- 3-1-(6-(2-(1-Methyl-1H-imidazole-4-sulfonylamino)-ethyl)-4-hydroxy-2-oxo-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is 2-(1-methylimidazole-4-sulfonylamino)-ethyl, R₂ ispropyl, R₃ is ethyl, R₄ is 1-methylimidazol-4-yl) Refer to Chart D

EXAMPLE 74

N- 3-1-(4-Hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-2-pyridinesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is phenethyl, R₃ is ethyl, R₄ is2-pyridyl) Refer to Chart D

EXAMPLE 75

4-Cyano-N- 3-1-(4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-2-pyridinesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is phenethyl, R₃ is ethyl, R₄ is4-cyano-2-pyridyl) Refer to Chart D

EXAMPLE 76

N- 3-1-(4-Hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-2-quinolinesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is phenethyl, R₃ is ethyl, R₄ isquinolin-2-yl) Refer to Chart D

EXAMPLE 77

2-Hydroxy-N- 3-1-(4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-benzenesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is phenethyl, R₃ is ethyl, R₄ is2-hydroxyphenyl) Refer to Chart D

EXAMPLE 78

N- 3-1-(4-Hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-2-pyrimidinesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is phenethyl, R₃ is ethyl, R₄ is2-pyrimidyl) Refer to Chart D

EXAMPLE 79

N- 3-1-(4-Hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-2-quinazolinesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is phenethyl, R₃ is ethyl, R₄ isquinazolin-2-yl) Refer to Chart D

EXAMPLE 80

N- 3-1-(4-Hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-7H-purine-6-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is phenethyl, R₃ is ethyl, R₄ is7H-purin-6-yl) Refer to Chart D

EXAMPLE 81

N- 3-1-(4-Hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1H-imidazole-2-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is phenethyl, R₃ is ethyl, R₄ is1H-imidazol-2-yl) Refer to Chart D

EXAMPLE 82

N- 3-1-(4-Hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1H-benzimidazole-2-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is phenethyl, R₃ is ethyl, R₄ is1H-benzimidazol-2-yl) Refer to Chart D

EXAMPLE 83

N- 3-1-(4-Hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-thiazole-4-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is phenethyl, R₃ is ethyl, R₄ isthiazol-2-yl) Refer to Chart D

EXAMPLE 84

N- 3-1-(4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-2-pyridinesulfonamide(Formula D-6: R₁ is propyl, R₂ is phenethyl, R₃ is ethyl, R₄ is2-pyridyl) Refer to Chart D

EXAMPLE 85

4-Cyano-N- 3-1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-2-pyridinesulfonamide(Formula D-6: R₁ is propyl, R₂ is phenethyl, R₃ is ethyl, R₄ is4-cyano-2-pyridyl) Refer to Chart D

EXAMPLE 86

N- 3-1-(4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-2-quinolinesulfonamide(Formula D-6: R₁ is propyl, R₂ is phenethyl, R₃ is ethyl, R₄ isquinolin-2-yl) Refer to Chart D

EXAMPLE 87

2-Hydroxy-N- 3-1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-benzenesulfonamide(Formula D-6: R₁ is propyl, R₂ is phenethyl, R₃ is ethyl, R₄ is2-hydroxyphenyl) Refer to Chart D

EXAMPLE 88

N- 3-1-(4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-2-pyrimidinesulfonamide(Formula D-6: R₁ is propyl, R₂ is phenethyl, R₃ is ethyl, R₄ is2-pyrimidyl) Refer to Chart D

EXAMPLE 89

N- 3-1-(4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-2-quinazolinesulfonamide(Formula D-6: R₁ is propyl, R₂ is phenethyl, R₃ is ethyl, R₄ isquinazolin-2-yl) Refer to Chart D

EXAMPLE 90

N- 3-1-(4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-7H-purine-6-sulfonamide(Formula D-6: R₁ is propyl, R₂ is phenethyl, R₃ is ethyl, R₄ is7H-purin-6-yl) Refer to Chart D

EXAMPLE 91

N- 3-1-(4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1H-imidazole-2-sulfonamide(Formula D-6: R₁ is propyl, R₂ is phenethyl, R₃ is ethyl, R₄ is1H-imidazol-2-yl) Refer to Chart D

EXAMPLE 92

N- 3-1-(4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-1H-benzimidazole-2-sulfonamide(Formula D-6: R₁ is propyl, R₂ is phenethyl, R₃ is ethyl, R₄ is1H-benzimidazol-2-yl) Refer to Chart D

EXAMPLE 93

N- 3-1-(4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-thiazole-4-sulfonamide(Formula D-6: R₁ is propyl, R₂ is phenethyl, R₃ is ethyl, R₄ isthiazol-2-yl) Refer to Chart D

EXAMPLE 93A

4-Fluoro-N- 3-1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-benzenesulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is4-fluorophenyl) Refer to Chart D

The title compound is prepared from the amine of Preparation 20 (FormulaD-5: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl) and 4-fluorobenzenesulfonyl chloride using the general procedure for sulfonylationof Example 40 to yield the title compound as an off-white amorphoussolid after flash chromatography with 5% EtOAc/CH₂ Cl₂.

Physical characteristics are as follows:

¹ H NMR complicated by presence of diastereomers.

¹ H NMR (300 MHz, CD₃ OD) δ0.75-0.96, 1.31-1.48, 1.57-2.01, 2.09-2.22,2.48-2.71, 3.92, 3.94, 6.86-7.24, 7.72.

PREPARATION 22

6-(2-Cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2H-pyran-2-one(Formula E-2) Refer to Chart E

To a cold (-78° C.) stirred solution of 1.5 ml of diisopropylamine in 9ml of dry tetrahydrofuran, under argon, is added 6.2 ml of a 1.6Msolution of n-butyllithium in hexane. The solution is warmed to 0° C.and then treated with a solution of 378 mg of commercially available4-hydroxy-6-methyl-2-pyrone of formula E-1 in 8 ml ofhexamethylphosphoramide. After 30 minutes at 0° C., 0.32 ml ofbromomethylcyclopropane is added; after another ten minutes, a secondportion of the same amount is added. The reaction is stirred, allowed towarm to room temperature overnight, and is then partitioned betweenethyl acetate and excess dilute hydrochloric acid. The organic phase iswashed with brine, dried over magnesium sulfate, and concentrated underreduced pressure. The residue is flash chromatographed on silica gel 60(230-400 mesh) using 25% ethyl acetate in dichloromethane containing 1%acetic acid to provide 371 mg of the title compound, along with 206 mgof monoalkylated material.

Physical characteristics are as follows:

¹ H NMR δ0.0, 0.4, 0.6, 1.5, 1.6, 2.2, 5.6, 6.1, 7.2-7.3, 11.5;

EI MS m/z=234;

TLC R_(f) 0.29 (25% ethyl acetate in dichloromethane containing 1%acetic acid).

PREPARATION 23

3-(α-Cyclopropyl-meta-(benzyloxycarbonylamino)benzyl)-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2H-pyran-2-one(Formula E-3) Refer to Chart E

A mixture of 367 mg of the title compound of Preparation 22, 470 mg ofthe title compound of Preparation F-5, 60 mg of p-toluenesulfonic acidmonohydrate, and 1 g of 3 Å molecular sieves in 5 ml of benzene isheated with stirring overnight under argon. The mixture is diluted withdichloromethane and ether and filtered through a pad of sodium sulfate.The solvent is removed under reduced pressure and the residue is flashchromatographed on silica gel 60 (230-400 mesh) using 5-20% ethylacetate in dichloromethane to afford 399 mg of the title compound.

Physical characteristics are as follows:

¹ H NMR δ-0.06, 0.3, 0.5, 1.4, 1.5, 2.5, 3.5, 5.1, 7.2-7.4;

EI HRMS m/z=513.2513;

TLC R_(f) 0.28 (5% ethyl acetate in dichloromethane).

PREPARATION 24

3-(α-Cyclopropyl-meta-aminobenzyl)-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2H-pyran-2-one(Formula E-4) Refer to Chart E

A mixture of 391 mg of the title compound of Preparation 23 and 100 mgof 5% palladium on carbon in 10 ml of methanol is shaken overnight under40 psi of hydrogen. The mixture is then filtered through Celite, and thefiltrate is concentrated under reduced pressure to provide 280 mg of thetitle compound.

Physical characteristics are as follows:

¹ H NMR δ0.0, 0.2-0.7, 1.4, 1.6, 1.8, 2.6, 6.8, 7.2-7.4;

TLC R_(f) 0.38 (30% ethyl acetate in dichloromethane.)

EXAMPLE 94

N-(3-{Cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-4-fluoro-benzenesulfonamide(Formula E-6) Refer to Chart E

To a mixture of 57 mg of the title compound of Preparation 24 and 24 μLof pyridine in 0.5 mL of dichloromethane is added 29 mg of4-fluorobenzenesulfonyl chloride. After stirring overnight, the solutionis diluted with ethyl acetate and washed with dilute aqueoushydrochloric acid, brine, dried over sodium sulfate, and concentratedunder reduced pressure. The residue is purified by flash columnchromatography on silica gel 60 (230-400 mesh) using 10% ethyl acetatein dichloromethane to give 56 mg of the title compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ-0.07, 0.13, 0.33, 0.54, 1.39, 1.51, 1.72, 2.55, 3.39,6.12, 6.87, 7.00, 7.08, 7.19, 7.27, 7.72, 9.72;

EI-MS: M+!=537.1977 found.

EXAMPLES 95-97

Following the procedure described above and using starting materials andreagents known and available to one of ordinary skill in organicsynthesis, the following additional compounds are prepared:

EXAMPLE 95

4-Cyano-N-(3-{cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-benzenesulfonamide(Formula E-7) Refer to Chart E

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ-0.03, 0.13, 0.23, 0.36, 0.44, 0.57, 1.41, 1.58, 1.75,2.57, 3.32, 5.98, 6.89, 7.11, 7.21, 7.68, 7.82;

EI-MS: M+!=544.2035 found.

EXAMPLE 96

N-(3-{Cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-8-quinolinesulfonamide(Formula E-8) Refer to Chart E

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ-0.07, 0.18, 0.37, 0.54, 1.37, 1.51, 2.53, 3.31, 5.96,6.87, 7.00, 7.13, 7.48, 7.54, 7.92, 8.23, 9.07;

EI-MS: M+!=570.2188 found.

EXAMPLE 97

N-(3-{Cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula E-9) Refer to Chart E

Physical characteristics are as follows:

¹ H-NMR (CDCl₃ --CD₃ OD) δ-0.08, 0.13, 0.33, 0.56, 1.37, 1.51, 1.73,2.54, 3.21, 3.60, 5.95, 6.82, 7.0, 7.19, 7.37, 7.5;

EI-MS: M+!=523.2142 found.

EXAMPLE 98

Chiral HPLC Separation of N-(3-{Cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula E-9) to give (R or S)-N-(3-{Cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula E-10) and (R or S)-N-(3-{Cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula E-11) Refer to Chart E

A stock sample of the title compound of Example 97 (3 mg/ml) in 5.0 mLeach of mobile phase (30% isopropanol, 0.1% acetic acid, and 0.2% waterin hexane) and isopropanol is prepared. The stock sample is filteredthrough a 0.45 micron syringe filter and washed with ethanol to give14.0 mL of clear filtrate. This solution is chromatographed on a 2.0×2.5cm (R,R) Whelk-O 1 (Regis Technologies, Inc., Morton Grove, Ill. 60053)column at 3.50 mL per injection using an automated chromatographicsystem. The eluant is monitored and the pools corresponding to thedesired peaks from multiple injections are combined, concentrated underreduced pressure and azeotroped with toluene. The residues are dissolvedin methanol, filtered through a syringe filter and the filtratesconcentrated under reduced pressure to give the title compounds (>95%pure):

(R or S)-N-(3-{Cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula E-10)

Physical characteristics are as follows:

¹ H-NMR (CDCl₃ --CD₃ OD) δ-0.07, 0.14, 0.34, 0.57, 1.32, 1.55, 1.75,2.51, 3.24, 3.60, 5.87, 6.85, 7.03, 7.15, 7.27, 7.37;

EI-MS: M+!=523.2149 found.

(R or S)-N-(3-{Cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula E-11)

Physical characteristics are as follows:

¹ H-NMR (CDCl₃ --CD₃ OD) δ-0.07, 0.14, 0.33, 0.55, 1.33, 1.56, 1.75,2.51, 3.23, 3.60, 5.88, 6.86, 7.03, 7.14, 7.27, 7.38;

EI-MS: M+!=523.2137 found.

EXAMPLES 99-103

Following the procedure described above and using starting materials andreagents known and available to one of ordinary skill in organicsynthesis, the following additional compounds are prepared:

EXAMPLE 99

N-(3-{Cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-pyridinesulfonamide(Formula E-12)

Physical characteristics are as follows:

¹ H-NMR (CDCl₃ --CD₃ OD) δ-0.05, 0.07, 0.17, 0.34, 0.55, 1.35, 1.55,1.7, 2.5, 3.24, 5.86, 6.90, 7.03, 7.15, 7.39, 7.78, 8.60;

EI-MS: M+!=520;

TLC R_(f) 0.35 (25% ethyl acetate in dichloromethane).

EXAMPLE 100

N-(3-{Cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-2-sulfonamide(Formula E-13)

Physical characteristics are as follows:

¹ H-NMR (CDCl₃ --CD₃ OD) δ-0.05, 0.15, 0.35, 0.56, 1.35, 1.55, 1.75,2.53, 3.23, 3.39, 5.89, 6.81, 6.90, 6.97, 7.09, 7.25;

EI-MS: M+!=523;

TLC R_(f) 0.31 (5% methanol in dichloromethane).

EXAMPLE 101

N-(3-{Cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1H-benzo-imidazole-2-sulfonamide(Formula E-14)

Physical characteristics are as follows:

¹ H-NMR (CDCl₃ --CD₃ OD) δ-0.07, 0.1, 0.15, 0.35, 0.56, 1.38, 1.58,1.65, 2.55, 3.28, 5.95, 6.73, 6.96, 7.10, 7.28, 7.58;

FAB-MS: M+H!=560.2220 found.

EXAMPLE 102

N-(3-{Cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1H-imidazole-2-sulfonamide(Formula E-15)

Physical characteristics are as follows:

¹ H-NMR (CDCl₃ --CD₃ OD) δ0.0, 0.25, 0.4, 0.6, 1.4, 1.6, 1.65, 2.6,3.35, 6.0, 6.8, 7.0, 7.2, 7.4;

EI-MS: M+!=509;

TLC R_(f) 0.25 (5% methanol in dichloromethane).

EXAMPLE 103

N-(3-{Cyclopropyl-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-quinolinesulfonamide(Formula E-16)

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ0.0, 0.2, 0.4, 0.6, 1.4, 1.6, 1.7, 2.6, 3.3, 6.0,7.0-7.2, 7.3, 7.7, 7.8-8.0, 8.2, 8.3;

EI-MS: M+!=570;

TLC R_(f) 0.53 (5% methanol in dichloromethane).

PREPARATION 25

Cyclopropyl meta-nitrophenyl ketone (Formula F-2) Refer to Chart F

A 250 ml three necked flask fitted with thermometer and addition funnelis charged with 130 ml of fuming 90% nitric acid and cooled to -10° C.Into the stirred liquid is added dropwise 21 ml of commerciallyavailable cyclopropyl phenyl ketone of formula F-1. The rate of additionis regulated to maintain the reaction temperature at about -10° C. Uponcompletion of addition, the resulting clear yellow solution is stirredfor another 10 minutes at -10° C., then poured into 1 L of crushed ice.The precipitated solid is extracted with 700 ml of toluene, and theextract is washed twice with 5% sodium hydroxide solution, once withbrine, and dried over magnesium sulfate. The solvent is removed underreduced pressure and the residue is recrystallized from methanol at -25°C. to give 14.6 g of the title compound as dense, pale yellow prisms.The mother liquor contained substantial amounts of the ortho isomer.

Physical characteristics are as follows:

¹ H NMR δ1.2, 1.3, 2.7, 7.70, 8.3, 8.4, 8.85;

IR 1664, 1529, 1352, 1225, 1082, 1017, 852, 689 cm⁻¹ ;

Anal. Found: C, 62.89; H, 4.73; N, 7.32;

EI MS m/z 191;

TLC R_(f) 0.32 (25% ethyl acetate in hexane).

PREPARATION 26

meta-Aminophenyl cyclopropyl ketone (Formula F-3) Refer to Chart F

A solution of 5.76 g of the title compound of Preparation 25 is preparedwith the aid of heat in 100 ml of methanol. To this is added 450 mg of5% platinum on carbon catalyst, and the mixture is stirred vigorouslyunder 1 atmosphere of hydrogen. After 5 hours, the mixture is filteredthrough a pad of Celite and the filtrate concentrated under reducedpressure to afford 4.89 g of the title compound as a greenish oil.

Physical characteristics are as follows:

¹ H NMR δ1.0, 1.2, 2.6, 3.9, 6.8, 7.2, 7.4;

TLC R_(f) 0.50 (80% ethyl acetate in hexane).

PREPARATION 27

meta-Benzyloxycarbonylaminophenyl cyclopropyl ketone (Formula F-4) Referto Chart F

To a cold (0° C.), stirred solution of 4.89 g of the title compound ofPreparation 26 and 6.3 ml of diisopropylethylamine in 90 ml ofdichloromethane is added dropwise 4.7 ml of benzyl chloroformate. Thecompleted solution is allowed to warm to room temperature. After 4hours, the mixture is washed with dilute hydrochloric acid, and theaqueous phase extracted with two additional portions of dichloromethane.The combined organic phase is dried over magnesium sulfate andconcentrated under reduced pressure to a yellow solid. This istriturated with two 30 ml portions of hexane, these being discarded, andthe remaining solid is dried under vacuum to afford 8.74 g of the titlecompound.

Physical characteristics are as follows:

TLC Rf 0.45 (5% ethyl acetate in dichloromethane).

PREPARATION 28

meta-Benzyloxycarbonylaminophenyl cyclopropyl carbinol (Formula F-5)Refer to Chart F

To a stirred solution of 8.74 g of compound F-4 of Preparation 27 in 100ml of tetrahydrofuran and 100 ml of ethanol is added, in portions, 4.5 gof sodium borohydride. After 3 hours at room temperature, the mixture iscooled in ice for the addition of 100 ml of 1N hydrochloric acid. Themixture is thrice extracted with dichloromethane, and the combinedextract dried over magnesium sulfate. Solvent is removed under reducedpressure and the residue flash chromatographed on silica gel 60 (230-400mesh) using 40% ethyl acetate in hexane to provide 8.48 g of the titlecompound as a white crystalline solid. This is optionally recrystallizedfrom ethyl acetate-hexane.

Physical characteristics are as follows:

¹ H NMR δ0.3-0.6, 1.1, 2.35, 3.92, 5.17, 7.1, 7.2-7.4;

IR 1693, 1599, 1559, 1449, 1235, 1054, 697 cm⁻¹ ;

Anal. Found: C, 72.57; H, 6.51; N, 4.61;

PREPARATION 29

4-Hydroxy-6- 3-(2-methoxy-ethoxy)-propyl!-pyran-2-one (Formula G-1)Refer to Chart G

To a flame-dried flask under an argon atmosphere is added 2.80 mL ofdiisopropylamine and 20.0 mL of dry tetrahydrofuran. The solution iscooled to -78° C. and treated with 12.5 mL (1.6M in hexane) ofn-butyllithium. The solution is warmed to 0° C. for 30 minutes, thentreated with 5.0 mL of dry hexamethylphosphoramide. The lithiumdiisopropylamide solution is then treated with 1.20 g of commerciallyavailable 4-hydroxy-6-methyl-2-pyrone of formula G-0 as a solution in 16mL of dry tetrahydrofuran and 14 mL of dry hexamethylphosphoramide.After 30 minutes the mixture is treated with 2.30 g of2-(2-methoxy-ethoxy)-ethyl iodide as a solution in 12 mL of drytetrahydrofuran. The mixture is stirred 1 hour at 0° C. and then warmedto room temperature. After 1 hour the reaction is quenched with excess1N aqueous hydrochloric acid. The mixture is concentrated under reducedpressure and partioned between dichloromethane and water. The aqueousphase is extracted with sufficient volumes of dichloromethane to removethe title compound. The combined organic extracts are washed with brine,dried over magnesium sulfate and concentrated under reduced pressure.The residue is purified by flash column chromatography on silica gel 60(230-400 mesh) eluting with 30% ethyl acetate in dichloromethanecontaining 3% acetic acid to 80% ethyl acetate in dichloromethanecontaining 5% acetic acid to give 1.34 g of the title compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ1.93, 2.54, 3.39, 3.55, 5.55, 5.90;

TLC R_(f) 0.26 (50% ethyl acetate in dichloromethane containing 5%acetic acid).

PREPARATION 30

3-(α-Cyclopropyl-meta-(benzyloxycarbonylamino)benzyl)-4-hydroxy-6-3-(2-methoxy-ethoxy)-propyl!-pyran-2-one (Formula G-2) Refer to Chart G

A mixture of 146 mg of the title compound of Preparation 29, 340 mg ofthe title compound of Preparation 28, prepared as described in Chart F,25 mg of p-toluenesulfonic acid monohydrate, and 0.5 g of 3 Å molecularsieves in 5 mL of dichloromethane is heated overnight with stirring. Themixture is cooled and the solvent removed under reduced pressure. Theresidue is purified by flash column chromatography on silica gel 60(230-400 mesh) eluting with 5% to 10% methanol in ethyl acetate to give129 mg of the title compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ0.25, 0.45, 0.67, 1.77, 2.39, 3.38, 3.51, 5.13, 5.84,7.17, 7.32, 7.42;

EI-MS: M+!=507.2257 found;

TLC R_(f) 0.28 (50% ethyl acetate in dichloromethane).

PREPARATION 31

3-(α-Cyclopropyl-meta-aminobenzyl)-4-hydroxy-6-3-(2-methoxy-ethoxy)-propyl!-pyran-2-one (Formula G-3) Refer to Chart G

A mixture of 124 mg of the title compound of Preparation 30 and 35 mg of5% palladium on charcoal in 5 mL of ethanol is shaken overnight under 50psi of hydrogen. The mixture is filtered through Celite with ethanolwashes of the filter cake. The filtrates are combined and the solventremoved under reduced pressure to give 92 mg of the title compound.Physical characteristics are as follows:

TLC R_(f) 0.12 (ethyl acetate).

EXAMPLE 104

N-(3-{Cyclopropyl-4-hydroxy-6-(3-{2-methoxy-ethoxy}-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula G-4) Refer to Chart G

To a mixture of 37 mg of the title compound of Preparation 31 and 18 μLof pyridine in 0.5 mL of dichloromethane is added 20 mg of1-methylimidazole-4-sulfonyl chloride. After stirring overnight, thesolvent is removed under reduced pressure. The residue is azeotropedwith toluene and is then purified by flash column chromatography onsilica gel 60 (230-400 mesh) using 2% to 8% methanol in dichloromethaneto give 32 mg of the title compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ0.1, 0.24, 0.45, 0.65, 1.75, 1.85, 2.46, 3.30, 3.34,3.50, 5.98, 6.98, 7.08, 7.19, 7.29, 7.42;

EI-MS: M+!=517.1874 found;

TLC R_(f) 0.22 (5% methanol in dichloromethane).

PREPARATION 32

3-(α-Cyclopropyl-meta-(benzyloxycarbonylamino)benzyl)-4-hydroxy-6-methyl-pyran-2-one(Formula H-1) Refer to Chart H

A mixture of 493 mg of commercially available4-hydroxy-6-methyl-2-pyrone of formula H-0, 592 mg of the title compoundof Preparation 28, prepared as described in Chart F and 56 mg ofp-toluenesulfonic acid monohydrate in 20 mL of dichloromethane is heatedto reflux through an addition funnel containing 3 Å molecular sieves for6 hours. The mixture is cooled and the solvent removed under reducedpressure. The residue is purified by flash column chromatography onsilica gel 60 (230-400 mesh) eluting with 60% to 100% ethyl acetate indichloromethane to give 470 mg of the title compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ0.23, 0.43, 0.66, 1.78, 3.41, 5.09, 5.89, 7.00, 7.14,7.29, 7.37, 10.1;

EI-MS: M+!=405;

TLC R_(f) 0.52 (ethyl acetate).

PREPARATION 33

3-(α-Cyclopropyl-meta-(benzyloxycarbonylamino)benzyl)-4-hydroxy-6-propyl-pyran-2-one(Formula H-2) Refer to Chart H

To a flame-dried flask under an argon atmosphere is added 0.45 mL ofdiisopropylamine and 3.0 mL of dry tetrahydrofuran. The solution iscooled to -78° C. and treated with 2.0 mL (1.6M in hexane) ofn-butyllithium. The solution is warmed to 0° C. for 15 minutes, thencooled to -78° C. The lithium diisopropylamide solution is treated with405 mg of the title compound of Preparation 32 as a solution in 4 mL ofdry tetrahydrofuran. After 1 hour at -78° C. the mixture is treated with85 μL of ethyl bromide. The mixture is then stirred at -78° C. for 3hours. The reaction is quenched with excess 1N aqueous hydrochloricacid. The mixture is warmed and partioned between ethyl acetate andphosphate buffer. The aqueous phase is extracted twice with ethylacetate. The combined organic extracts are dried over magnesium sulfateand concentrated under reduced pressure. The residue is purified byflash column chromatography on silica gel 60 (230-400 mesh) eluting with10% to 20% ethyl acetate in dichloromethane to give 277 mg of the titlecompound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ0.24, 0.45, 0.65, 0.88, 1.55, 1.79, 2.28, 3.42, 5.10,5.95, 6.89, 7.15, 7.3, 10.0;

EI-MS: M+!=433;

TLC R_(f) 0.33 (10% ethyl acetate in dichloromethane).

PREPARATION 34

3-(α-Cyclopropyl-meta-(benzyloxycarbonylamino)benzyl)-6-1-ethyl-3-(2-methoxy-ethoxy)-propyl!-4-hydroxy-pyran-2-one (Formula H-3)Refer to Chart H

To a flame-dried flask under an argon atmosphere is added 0.30 mL ofdiisopropylamine and 2.0 mL of dry tetrahydrofuran. The solution iscooled to -78° C. and treated with 1.3 mL (1.6M in hexane) ofn-butyllithium. The solution is warmed to 0° C. for 15 minutes, thencooled to -78° C. The lithium diisopropylamide solution is treated with277 mg of the title compound of Preparation 33 as a solution in 3 mL ofdry tetrahydrofuran. After 1 hour at -78° C., the mixture is treatedwith 180 mg of 2-(2-methoxy-ethoxy)-ethyl iodide in 3 mL oftetrahydrofuran. The mixture is then stirred at -78° C. for 3 hours. Thereaction is quenched with excess 1N aqueous hydrochloric acid. Themixture is warmed and partioned between ethyl acetate and phosphatebuffer. The aqueous phase is extracted thrice with ethyl acetate. Thecombined organic extracts are washed with brine, dried over magnesiumsulfate and concentrated under reduced pressure. The residue is purifiedby flash column chromatography on silica gel 60 (230-400 mesh) elutingwith 25% to 40% ethyl acetate in dichloromethane to give 198 mg of thetitle compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ0.25, 0.46, 0.66, 0.75, 1.5, 1.76, 2.36, 3.4, 5.15,5.96, 7.2, 7.3, 7.42, 10.0;

EI-MS: M+!=535;

TLC R_(f) 0.29 (25% ethyl acetate in dichloromethane).

PREPARATION 35

3-(α-Cyclopropyl-meta-aminobenzyl)-6-1-ethyl-3-(2-methoxy-ethoxy)-propyl!-4-hydroxy-pyran-2-one (Formula H-4)Refer to Chart H

A mixture of 180 mg of the title compound of Preparation 34 and 50 mg of5% palladium on charcoal in 2 mL of ethanol is shaken overnight under 50psi of hydrogen. The mixture is filtered through Celite with ethanolwashes of the filter cake. The filtrates are combined and the solventremoved under reduced pressure to give 127 mg of the title compound.

Physical characteristics are as follows:

TLC R_(f) 0.19 (ethyl acetate).

EXAMPLE 105

N-(3-{Cyclopropyl-6-(1-ethyl-3-{2-methoxy-ethoxy}-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula H-5) Refer to Chart H

To a mixture of 32 mg of the title compound of Preparation 35 and 13 μLof pyridine in 0.8 mL of dichloromethane is added 14.5 mg of1-methylimidazole-4-sulfonyl chloride. After stirring overnight, thesolvent is removed under reduced pressure. The residue is azeotropedwith toluene and is then purified by flash column chromatography onsilica gel 60 (230-400 mesh) using 1% to 4% methanol in dichloromethaneto give 38 mg of the title compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ0.05, 0.25, 0.45, 0.65, 0.83, 1.5-2.0, 2.45, 3.3-3.5,3.62, 6.00, 6.99, 7.1-7.3, 7.48;

EI-MS: M+!=545.2186 found;

TLC R_(f) 0.24 (5% methanol in dichloromethane).

EXAMPLE 106

4-Cyano-N-(3-{cyclopropyl-6-(1-ethyl-3-{2-methoxy-ethoxy}-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-benzenesulfonamide

Following the procedure described above and using starting materials andreagents known and available to one of ordinary skill in organicsynthesis, the title compound is prepared.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ0.15, 0.25, 0.45, 0.65, 0.78, 1.2-1.8, 2.4, 3.3-3.6,3.54, 5.89, 6.95, 7.1-7.3, 7.6-7.9;

FAB-MS: M+H!=567.2176 found;

TLC R_(f) 0.40 (50% ethyl acetate in dichloromethane).

PREPARATION 36

3-(α-Cyclopropyl-meta-(benzyloxycarbonylamino)benzyl)-6-(1-ethyl-3-hydroxy-propyl)-4-hydroxy-pyran-2-one(Formula I-1) Refer to Chart I

To a flame-dried flask under an argon atmosphere is added 0.46 mL ofdiisopropylamine and 3.5 mL of dry tetrahydrofuran. The solution iscooled to -78° C. and treated with 2.0 mL (1.6M in hexane) ofn-butyllithium. The solution is warmed to 0° C. for 20 minutes, thencooled to -78° C. The lithium diisopropylamide solution is treated with433 mg of the title compound of Preparation 33 as a solution in 4 mL ofdry tetrahydrofuran. After 1 hour at -78° C. the mixture is treated withgaseous ethylene oxide for 5 minutes. The mixture is then stirred at-78° C. for 15 minutes. The reaction is quenched with excess 1N aqueoushydrochloric acid. The mixture is warmed and partioned betweendichloromethane and phosphate buffer. The aqueous phase is extractedtwice with dichloromethane. The combined organic extracts are washedwith brine, dried over magnesium sulfate and concentrated under reducedpressure. The residue is purified by flash column chromatography onsilica gel 60 (230-400 mesh) eluting with 2% to 8% methanol indichloromethane to give 144 mg of the title compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ0.22, 0.45, 0.65, 0.7, 1.3-1.7, 1.8, 2.25, 3.4, 5.1,5.91, 7.1-7.4;

FAB-MS: M+H!=478;

TLC R_(f) 0.29 (5% methanol in dichloromethane).

PREPARATION 37

6-(3-Bromo-1-ethyl-propyl)-3-(α-cyclopropyl-meta-(benzyloxycarbonylamino)benzyl)-4-hydroxy-pyran-2-one(Formula I-2) Refer to Chart I

To a stirring solution of 114 mg of the title compound of Preparation 36in 3 mL of tetrahydrofuran is added 160 mg of triphenylphosphine and 200mg of carbon tetrabromide. After 2 hours, the solvent is removed underreduced pressure and the residue is purified by flash columnchromatography on silica gel 60 (230-400 mesh) eluting with 70% to 100%diethyl ether in hexane to give 113 mg of the title compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ0.25, 0.35, 0.55, 0.65, 0.84, 1.5-2.2, 3.2, 3.35, 3.52,5.16, 5.95, 6.79, 7.1-7.4;

FAB-MS: M+H!=504.1404 found;

TLC R_(f) 0.29 (75% diethyl ether in hexane).

PREPARATION 38

6-(3-Azido-1-ethyl-propyl)-3-(α-cyclopropyl-meta-(benzyloxycarbonylamino)benzyl)-4-hydroxy-pyran-2-one(Formula I-3) Refer to Chart I

To a stirring solution of 113 mg of the title compound of Preparation 37in 2.0 mL of ethanol is added 55 mg of sodium azide and 0.5 mL of water.The reaction mixture is heated overnight and then cooled. The solvent isremoved under reduced pressure and the residue is purified by flashcolumn chromatography on silica gel 60 (230-400 mesh) eluting withdiethyl ether to give 89 mg of the title compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ0.23, 0.33, 0.51, 0.68, 0.82, 1.4-2.0, 2.33, 3.1-3.3,3.5, 5.15, 5.94, 6.84, 7.1-7.4;

EI-MS: M+!=502;

TLC R_(f) 0.52 (10% ethyl acetate in dichloromethane).

PREPARATION 39

6-(3-Amino-1-ethyl-propyl)-3-(α-cyclopropyl-meta-aminobenzyl)-4-hydroxy-pyran-2-one(Formula I-4) Refer to Chart I

A mixture of 87 mg of the title compound of Preparation 38 and 35 mg of5% palladium on charcoal in 4 mL of ethanol is shaken for 4 hours under40 psi of hydrogen. The mixture is filtered through Celite with ethanolwashes of the filter cake. The filtrates are combined and the solventremoved under reduced pressure to give 70 mg of the title compound as amixture with6-(3-amino-1-ethyl-propyl)-3-(α-cyclopropyl-meta-(benzyloxycarbonylamino)benzyl)-4-hydroxy-pyran-2-one.

Physical characteristics are as follows:

TLC R_(f) 0.05 (5% methanol in dichloromethane).

PREPARATION 40

3-(Cyclopropyl-{3-1-methyl-1H-imidazole-4-sulfonylamino!-phenyl}-methyl)-6-({1-ethyl-3-1-methyl-1H-imidazole-4-sulfonylamino!}-propyl)-2-oxo-2H-pyran-4-yl1-methyl-1H-imidazole-4-sulfonate (Formula I-5) Refer to Chart I

To a mixture of 70 mg of the title compound of Preparation 39 and6-(3-amino-1-ethyl-propyl)-3-(α-cyclopropyl-meta-(benzyloxycarbonylamino)benzyl)-4-hydroxy-pyran-2-one,also from Preparation 39, in 1.5 mL of dichloromethane is added 120 μLof diisopropylethylamine and 92 mg of 1-methylimidazole-4-sulfonylchloride. After stirring overnight, the solvent is removed under reducedpressure. The residue is azeotroped with toluene and is then purified byflash column chromatography on silica gel 60 (230-400 mesh) using 2% to6% methanol in dichloromethane to give 49 mg of the title compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ0.2-0.5, 0.75, 0.90, 1.4-2.0, 2.55, 3.0-3.4, 3.6-3.7,6.63, 7.0-7.7;

TLC R_(f) 0.14 (5% methanol in dichloromethane).

EXAMPLE 107

N-(3-{Cyclopropyl-6-(1-ethyl-3-{1-methyl-1H-imidazole-4-sulfonylamino}-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula I-6) Refer to Chart I

A solution of 49 mg of the title compound of Preparation 40 in 4 mLmethanol containing ammonia is cooled to 0° C. and treated with gaseousammonia. After 5 minutes ammonia introduction is ceased, the flask istightly capped and warmed to room temperature. After standing overnightthe solvent is removed under reduced pressure and the residue ispurified by flash column chromatography on silica gel 60 (230-400 mesh)eluting with 3% to 9% methanol in dichloromethane to give 32 mg of thetitle compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ0.2-0.5, 0.75, 0.90, 1.4-2.0, 2.55, 3.0-3.4, 3.6-3.7,6.63, 7.0-7.7;

EI-MS: M+!=523;

TLC R_(f) 0.33 (5% methanol in dichloromethane).

PREPARATION 41

3-(α-Cyclopropyl-meta-aminobenzyl)-6-(1-ethyl-3-hydroxypropyl)-4-hydroxy-pyran-2-one(Formula J-1) Refer to Chart J

A mixture of 477 mg of the title compound of Preparation 36 and 150 mgof 5% palladium on charcoal in 10 mL of ethanol is shaken overnightunder 45 psi of hydrogen. The mixture is filtered through Celite withethanol washes of the filter cake. The filtrates are combined and thesolvent is removed under reduced pressure to give 340 mg of the titlecompound.

Physical characteristics are as follows:

TLC R_(f) 0.10 (5% methanol in dichloromethane).

PREPARATION 42

6-(3-Bromo-1-ethyl-propyl)-3-(α-cyclopropyl-meta-aminobenzyl)-4-hydroxy-pyran-2-one(Formula J-2) Refer to Chart J

To a stirring solution of 340 mg of the title compound of Preparation 41in 7 mL of tetrahydrofuran is added 525 mg of triphenylphosphine and 663mg of carbon tetrabromide. After 30 minutes, the solvent is removedunder reduced pressure and the residue is purified by flash columnchromatography on silica gel 60 (230-400 mesh) eluting with 30% to 50%ethyl acetate in dichloromethane to give 228 mg of the title compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃) δ0.19, 0.42, 0.58, 0.75, 1.4-2.4, 3.14, 3.3, 5.26, 6.15,6.47, 6.91, 7.00;

TLC R_(f) 0.45 (5% methanol in dichloromethane).

EXAMPLE 108

N-(3-{6-(3-Bromo-1-ethyl-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-cyclopropyl-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula J-3) Refer to Chart J

To a mixture of 102 mg of the title compound of Preparation 42 and 40 μLof pyridine in 1.0 mL of dichloromethane is added 45 mg of1-methylimidazole-4-sulfonyl chloride. After stirring overnight, thesolvent is removed under reduced pressure. The residue is azeotropedwith toluene and is then purified by flash column chromatography onsilica gel 60 (230-400 mesh) using 2% to 5% methanol in dichloromethaneto give 86 mg of the title compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃ --CD₃ OD) δ0.2, 0.44, 0.60, 0.82, 1.4-2.2, 2.5, 3.1-3.4,3.62, 5.93, 6.92, 7.07, 7.19, 7.30, 7.40;

FAB-MS: M+H!=550.1037 found;

TLC R_(f) 0.36 (5% methanol in dichloromethane).

EXAMPLE 109

N-(3-}6-(3-Azido-1-ethyl-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-cyclopropyl-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula J-4) Refer to Chart J

To a stirring solution of 113 mg of the title compound of Example 108 in1.2 mL of ethanol is added 50 mg of sodium azide and 0.4 mL of water.The reaction mixture is heated overnight and then cooled. The solvent isremoved under reduced pressure and the residue is purified by flashcolumn chromatography on silica gel 60 (230-400 mesh) eluting with 3% to6% methanol in dichloromethane to give 57 mg of the title compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃ --CD₃ OD) δ0.25, 0.48, 0.66, 0.90, 1.3-1.8, 2.42,2.9-3.2, 3.68, 5.94, 6.93, 7.12, 7.19, 7.23, 7.35, 7.46;

FAB-MS: M+H!=550.1037 found;

TLC R_(f) 0.36 (5% methanol in dichloromethane).

PREPARATION 43

N-(3-{6-(3-Amino-1-ethyl-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-cyclopropyl-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula J-5) Refer to Chart J

A mixture of 104 mg of the title compound of Example 109 and 30 mg of 5%palladium on charcoal in 2 mL of each of methanol and ethanol is shakenovernight under 45 psi of hydrogen. The mixture is filtered throughCelite with methanol washes of the filter cake. The filtrates arecombined and the solvent is removed under reduced pressure to give 69 mgof the title compound.

Physical characteristics are as follows:

TLC R_(f) 0.05 (5% methanol in dichloromethane).

EXAMPLE 110

2- 8- 3- 3- Cyclopropyl 3-(1-methyl-1H-imidazol-4-yl)sulfonyl!amino!phenyl!methyl!-4-hydroxy-2-oxo-2H-pyran-6-yl!pentyl!amino!-1,8-dioxooctyl!methylamino!-ethanesulfonic acid, monosodium salt (Formula J-6) Refer to Chart J

A suspension of 69 mg of the title compound of Preparation 43 in 1.0 mLof dichloromethane is treated with 0.22 mL (0.65M in acetonitrile) ofthe triethylamine salt of suleptanic acid and 25 μL ofdiisopropylcarbodiimide. After 1 hour the mixture is treated with 0.5 mLof dimethylformamide. After stirring overnight the solvent is removedunder reduced pressure and the residue is purified by flash columnchromatography on silica gel 60 (230-400 mesh) eluting with 10% to 30%methanol in dichloromethane. The crude product is dissolved in watersaturated n-butanol and partioned with saturated aqueous sodium sulfate.The aqueous phase is extracted twice with additional portions of watersaturated n-butanol. The combined n-butanol layers are filtered througha pad of sodium sulfate and concentrated under reduced pressure to give94 mg of the title compound.

Physical characteristics are as follows:

¹ H-NMR (CDCl₃ --CD₃ OD) δ0.05-0.6, 0.83, 1.1-2.5, 2.9-3.7, 3.68, 5.84,6.8-7.6;

FAB-MS: M+H!=786.2838 found;

TLC R_(f) 0.21 (20% methanol in dichloromethane).

EXAMPLES 111-134

Utilizing procedures described above and using starting materials andreagents known and available to one of ordinary skill in organicsynthesis, the following additional compounds are prepared:

111) N-(3-{Cyclopropyl- 4-hydroxy-6-(3-{(2-hydroxy-1,1-bis{hydroxymethyl}-ethyl)-amino!-carbonyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-benzenesulfonamide

112) N-(3-{Cyclopropyl- 4-hydroxy-6-(3-{(2-hydroxy-1,1-bis{hydroxymethyl}-ethyl)-amino!-carbonyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-pyridinesulfonamide

113) N-(3-{Cyclopropyl- 4-hydroxy-6-(3-{(2-hydroxy-1,1-bis{hydroxymethyl}-ethyl)-amino!-carbonyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1H-imidazole-2-sulfonamide

114) N-(3-{Cyclopropyl- 4-hydroxy-6-(3-{(2-hydroxy-1,1-bis{hydroxymethyl}-ethyl)-amino!-carbonyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1H-benzoimidazole-2-sulfonamide

115) N-(3-{Cyclopropyl- 4-hydroxy-6-(3-{(2-hydroxy-1,1-bis{hydroxymethyl}-ethyl)-amino!-carbonyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide

116) N-(3-{Cyclopropyl- 4-hydroxy-6-(3-{(2-hydroxy-1,1-bis{hydroxymethyl}-ethyl)-amino!-carbonyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-2-sulfonamide

117) N-(3-{Cyclopropyl-4-hydroxy-6-(3-{γ-L-glutamyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-benzenesulfonamide

118) N-(3-{Cyclopropyl-4-hydroxy-6-(3-{γ-L-glutamyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-pyridinesulfonamide

119) N-(3-{Cyclopropyl-4-hydroxy-6-(3-{γ-L-glutamyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1H-imidazole-sulfonamide

120) N-(3-{Cyclopropyl-4-hydroxy-6-(3-{γ-L-glutamyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1H-benzoimidazole-sulfonamide

121) N-(3-{Cyclopropyl-4-hydroxy-6-(3-{γ-L-glutamyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide

122) N-(3-{Cyclopropyl-4-hydroxy-6-(3-{γ-L-glutamyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-2-sulfonamide

123) N-(3-{Cyclopropyl- 4-hydroxy-6-(3-{piperazin-1-yl!-carbonyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-benzenesulfonamide

124) N-(3-{Cyclopropyl- 4-hydroxy-6-(3-{piperazin-1-yl!-carbonyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-pyridinesulfonamide

125) N-(3-{Cyclopropyl- 4-hydroxy-6-(3-{piperazin-1-yl!-carbonyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1H-imidazole-2-sulfonamide

126) N-(3-{Cyclopropyl- 4-hydroxy-6-(3-{piperazin-1-yl!-carbonyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1H-benzoimidazole-2-sulfonamide

127) N-(3-{Cyclopropyl- 4-hydroxy-6-(3-{piperazin-1-yl!-carbonyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide

128) N-(3-{Cyclopropyl- 4-hydroxy-6-(3-{piperazin-1-yl!-carbonyl}-amino-propyl)-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-2-sulfonamide

129) 2- 8- 3- 3- Cyclopropyl 3-phenylsulfonyl!amino!phenyl!methyl!-4-hydroxy-2-oxo-2H-pyran-6-yl!propyl!amino!-1,8-dioxooctyl!methylamino!-ethanesulfonicacid, monosodium salt

130) 2- 8- 3- 3- Cyclopropyl 3-(2-pyridyl)sulfonyl!amino!phenyl!methyl!-4-hydroxy-2-oxo-2H-pyran-6-yl!propyl!amino!-1,8-dioxooctyl!methylamino!-ethanesulfonic acid, monosodium salt

131) 2- 8- 3- 3- Cyclopropyl 3-(1H-benzimidazol-2-yl)sulfonyl!amino!phenyl!methyl!-4-hydroxy-2-oxo-2H-pyran-6-yl!propyl!amino!-1,8-dioxooctyl!methylamino!-ethanesulfonic acid, monosodium salt

132) 2- 8- 3- 3- Cyclopropyl 3-(1H-imidazol-2-yl)sulfonyl!amino!phenyl!methyl!-4-hydroxy-2-oxo-2H-pyran-6-yl!propyl!amino!-1,8-dioxooctyl!methylamino!-ethanesulfonic acid, monosodium salt

133) 2- 8- 3- 3- Cyclopropyl 3-(1-methyl-1H-imidazol-4-yl)sulfonyl!amino!phenyl!methyl!-4-hydroxy-2-oxo-2H-pyran-6-yl!propyl!amino!-1,8-dioxooctyl!methylamino!-ethanesulfonicacid, monosodium salt

134) 2- 8- 3- 3- Cyclopropyl 3-(1-methyl-1H-imidazol-2-yl)sulfonyl!amino!phenyl!methyl!-4-hydroxy-2-oxo-2H-pyran-6-yl!propyl!amino!-1,8-dioxooctyl!methylamino!-ethanesulfonic acid, monosodium salt

PREPARATION 44

(Tetrahydropyran-4-yl)-methanol (Formula K-2) Refer to Chart K

To a cold (0°), stirred solution of 651 mg oftetrahydropyran-4-carboxylic acid in 2.5 ml of dry tetrahydrofuran,under argon, is added dropwise 10 ml of a 1.0M solution of borane intetrahydrofuran. After 18 hours at room temperature, the solution isrecooled to 0° and quenched with 1 ml of 1M KOH. The mixture isacidified with 1M aqueous hydrochloric acid and extracted four timeswith dichloromethane. The extract is dried over magnesium sulfate andconcentrated carefully under reduced pressure to afford 0.72 g of thealcohol as a colorless liquid.

Physical characteristics are as follows:

¹ H NMR δ1.2-1.4, 1.6, 1.8, 3.3-3.4, 3.6, 4.0 ppm.

PREPARATION 45

(Tetrahydropyran-4-yl)-methyl p-toluenesulfonate (Formula K-3) Refer toChart K

To a cold (0°), stirred solution of 5 mmol of the title compound ofPreparation 44 and 0.81 ml of pyridine in 5 ml of dichloromethane isadded 1.05 g of p-toluenesulfonyl chloride, and the solution is allowedto warm to room temperature. After 18 hours the mixture is partitionedbetween ethyl acetate and dilute aqueous hydrochloric acid, and theorganic phase is washed with brine and dried over magnesium sulfate.Following removal of solvent under reduced pressure, the residue isflash chromatographed on silica using 50% ethyl acetate in hexane toafford 1.23 g of the title compound as a colorless liquid.

Physical characteristics are as follows:

¹ H NMR δ1.2-1.4, 1.6, 1.9-2.0, 2.46, 3.34, 3.85, 3.95, 7.3, 7.8 ppm.

MS: 270

PREPARATION 46

(Tetrahydropyran-4-yl)-methyl iodide (Formula K-4) Refer to Chart K

A solution of 800 mg of tosylate of Preparation 45 and 887 mg of sodiumiodide in 6 ml of acetone is refluxed under nitrogen for six hours, thenpartitioned between ether and dilute aqueous sodium thiosulfate. Theorganic phase is washed with brine, dried over magnesium sulfate, andconcentrated carefully under atmospheric pressure to give 648 mg of theiodide as a colorless liquid.

Physical characteristics are as follows:

¹ H NMR δ1.2-1.4, 1.6-1.9, 3.1, 3.37, 3.97 ppm.

PREPARATION 47

6-(1-(Tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxypyran-2-one (FormulaK-5) Refer to Chart K

To a cold (-78°) stirred solution of 0.90 ml of diisopropylamine in 5 mlof tetrahydrofuran, under argon, is added via syringe 3.7 ml of a 1.6Msolution of n-butyllithium in hexane. The solution is warmed to 0°, andafter ten minutes, a solution of 431 mg of the title compound ofPreparation 50 in 3 ml of hexamethylphosphoramide is added via cannula.After 20 minutes, the deep red solution is cooled to -50°, and 605 mg ofiodide of Preparation 46 in 1 ml of tetrahydrofuran is added viacannula. The reaction is allowed to warm slowly to 0° and then quenchedby addition of pH 7 phosphate buffer. Following removal oftetrahydrofuran under reduced pressure, the residual liquid is acidifiedwith dilute aqueous hydrochloric acid and the resulting precipitateextracted with two portions of ethyl acetate. The organic is washed withdilute aqueous hydrochloric acid and brine, dried over magnesiumsulfate, and concentrated under reduced pressure. Flash chromatographyof the residue on silica using 5% acetic acid and 30-40% ethyl acetatein dichloromethane provides 553 mg of the title compound as a thickyellow gum.

Physical characteristics are as follows:

TLC R_(f) 0.36 (5% acetic acid, 65% ethyl acetate in dichloromethane)

¹ H NMR δ0.85, 1.2-1.8, 2.45, 3.34, 3.9, 5.56, 5.94 ppm.

MS: 252

PREPARATION 48

3-(3-Benzyloxycarbonylaminophenyl)-cyclopropylmethyl!-6-(1-(tetrahydropyran-4-ylmethyl)-propyl-4-hydroxy-pyran-2-one(Formula K-6) Refer to Chart K

A solution of 549 mg of alkylation product of Preparation 47, 970 mg of3-benzyloxycarbonylaminophenyl cyclopropyl carbinol, and 60 mg ofp-toluenesulfonic acid monohydrate in 5 ml of dichloromethane isrefluxed through 10 ml of 3 Å sieves for 18 hours. Following removal ofsolvent under reduced pressure, the residue is flash chromatographed onsilica using 25-100% ethyl acetate in dichloromethane to 5% methanol inethyl acetate, providing 511 mg of the title compound as a tan solid.

Physical characteristics are as follows:

TLC R_(f) 0.32 (30% ethyl acetate in dichloromethane)

¹ H NMR δ0.2, 0.5, 0.7, 0.8, 1.3-1.7, 3.27, 3.42, 3.86, 5.13, 5.96,7.1-7.4 ppm.

MS: 531

PREPARATION 49

3-(3-Aminophenyl)-cyclopropylmethyl!-6-(1-(tetrahydropyran-4-ylmethyl)-propyl-4-hydroxy-pyran-2-one(Formula K-7) Refer to Chart K

A mixture of 510 mg of the title compound of Preparation 48, 605 mg ofammonium formate, and 100 mg of 5% palladium on carbon in 8 ml ofmethanol is stirred under argon for three hours, then filtered throughdiatomaceous earth. The filtrate is concentrated under reduced pressure,and the residue flash chromatographed on silica using 2-4% methanol indichloromethane to afford 280 mg of the title amine as a white solid.

Physical characteristics are as follows:

TLC R_(f) 0.33 (5% methanol in dichloromethane)

¹ H NMR δ0.24, 0.42, 0.53, 0.68, 0.84, 1.1-1.7, 2.35, 3.33, 3.6, 3.9,5.82, 6.5, 6.83, 6.9, 7.11 ppm.

EXAMPLE 135

N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula K-8) Refer to Chart K

To a stirred solution of 60 mg of the amine of Preparation 49 and 24 μLof pyridine in 0.5 ml of dichloromethane is added 27 mg of1-methylimidazole-4-sulfonyl chloride. After 18 hours the reaction isflashed on silica using 3-6% methanol in dichloromethane to afford 70 mgof the title compound as a white solid.

Physical characteristics are as follows:

TLC R_(f) 0.24 (5% methanol in dichloromethane)

¹ H NMR δ0.12, 0.26, 0.45, 0.60, 0.82, 1.1-1.9, 2.3, 3.3, 3.58, 3.9,6.00, 6.9-7.5 ppm.

HRMS: 541.2238

PREPARATION 50

4-Hydroxy-6-propylpyran-2-one (Formula K-9) Refer to Chart K

To a cold (-78°), stirred solution of 6.3 ml of diisopropylamine in 40ml of dry tetrahydrofuran, under argon, is added 27.5 ml of a 1.6Msolution of butyllithium in hexane. The solution is brought to 0°, andinto this is cannulated a solution of 2.52 g of4-hydroxy-6-methyl-2-pyrone of formula K-10 in 20 ml ofhexamethylphosphoric triamide. The deep red solution is stirred 30minutes at 0°, then cooled to -45° for the addition of 1.5 ml of ethylbromide. The solution is warmed to 0° and quenched with 60 ml of 1Naqueous hydrochloric acid. Tetrahydrofuran is removed under reducedpressure and the residue extracted five times with ethyl acetate. Theorganic phase is washed with brine, dried over magnesium sulfate, andconcentrated under reduced pressure. Flash chromatography of the residueon silica gel using 4% acetic acid and 16% ethyl acetate indichloromethane provides 2.34 g of the title compound as a waxy yellowsolid.

Physical characteristics are as follows:

TLC R_(f) 0.29 (5% acetic acid and 15% ethyl acetate in dichloromethane)

¹ H NMR δ0.98, 1.6, 2.4, 5.63, 6.05

PREPARATION 51

4-Hydroxy-6-phenethyl-2H-pyran-2-one (Formula L-2) Refer to Chart L

To a flame-dried flask containing a stirred solution of 0.90 mL ofdiisopropylamine in 6 mL of anhydrous tetrahydrofuran at -78° C. underan argon atmosphere is added 4.0 mL of a 1.6M solution of n-butyllithiumin hexane. The resulting solution is allowed to warm to 0° C. for 20min, and is then treated via cannula with a solution of 378 mg ofcommercially available 4-hydroxy-6-methyl-2-pyrone of formula L-1 in 15mL of tetrahydrofuran. The resulting red, thick slurry is slowly treatedwith 6.0 mL of distilled hexamethylphosphoramide and allowed to stir for30 min. The red, cloudy solution is then treated with 0.36 mL of benzylbromide. The reaction quickly becomes a deep orange solution and isallowed to stir at 0° C. for an additional 60 min. The mixture isquenched with excess 1N aqueous hydrochloric acid and the resultingyellow, biphasic mixture is concentrated to remove the tetrahydrofuran.The resulting mixture is partitioned between dichloromethane and waterand the acidic aqueous phase is further extracted with additionalportions of dichloromethane. The combined organic phase is dried overmagnesium sulfate and then concentrated under reduced pressure. Theresulting material is diluted with a large volume of diethyl ether andwashed with dilute aqueous hydrochloric acid. The ethereal phase iswashed with two additional portions of aqueous hydrochloric acid, oncewith brine, dried over magnesium sulfate, and finally concentrated underreduced pressure. The residue is flash column chromatographed on silicagel 60 (230-400 mesh) eluting with 1% acetic acid and 20% to 40% ethylacetate in dichloromethane to give 440 mg of the title compound as a tansolid.

Physical characteristics are as follows:

¹ H NMR δ2.7, 3.0, 5.46, 5.84, 7.1-7.3.

TLC R_(f) 0.38 (1% acetic acid and 25% ethyl acetate indichloromethane.)

MP 137°-138° C.

PREPARATION 52

6-(α-Ethyl-phenethyl)-4-hydroxy-2H-pyran-2-one (Formula L-3) Refer toChart L

To a cold (-78° C.) stirred solution of 0.29 ml of diisopropylamine in 4ml of dry tetrahydrofuran, under argon, is added 1.2 ml of a 1.6Msolution of n-butyllithium in hexane. The solution is warmed to 0° C.,kept at that temperature for ten minutes, then cooled to -30° C. Intothis solution is cannulated a solution of 189 mg of the title compoundof Preparation 51 in 4 ml of tetrahydrofuran. The resultingheterogeneous mixture is warmed to 0°, and sufficienthexamethylphosphoramide (ca 1 ml) is added to render the mixture mostlyhomogeneous. After the mixture is stirred for 30 minutes at 0° C., 77 μLof ethyl iodide is added dropwise. After another 90 minutes, thereaction is quenched with excess 1N aqueous hydrochloric acid, andtetrahydrofuran is removed under reduced pressure. The residue isextracted with three portions of ethyl acetate, and the combined organicextract washed with dilute aqueous hydrochloric acid, dried overmagnesium sulfate, and concentrated under reduced pressure. The residueis flash chromatographed on silica gel 60 (230-400 mesh) using 1% aceticacid and 25% ethyl acetate in dichloromethane to provide 182 mg of thetitle compound.

Physical characteristics are as follows:

¹ H NMR δ0.85, 1.6, 2.6, 2.9, 5.59, 5.86, 7.0-7.3.

FAB MS m+H!=245.1185.

TLC R_(f) 0.33 (1% acetic acid and 25% ethyl acetate indichloromethane.)

PREPARATION 53

3-(α-Cyclopropyl-meta-(benzyloxycarbonylamino)benzyl)-6-(α-ethyl-phenethyl)-4-hydroxy-2H-pyran-2-one(Formula L-4) Refer to Chart L

A mixture of 181 mg of the title compound of Preparation 52, 220 mg ofthe compound of formula F-5, 28 mg of p-toluenesulfonic acidmonohydrate, and 600 mg of 3 Å molecular sieves in 2 ml of benzene isrefluxed under argon for 21 hours, then cooled and filtered throughCelite. The filtrate is concentrated under reduced pressure, and theresidue flash chromatographed on silica gel 60 (230-400 mesh) using50-100% ethyl acetate in hexane to provide 250 mg of a mixture ofmaterials. This is re-subjected to silica gel chromatography, using5-20% ethyl acetate in dichloromethane, to afford 154 mg (40%) of thetitle compound.

Physical characteristics are as follows:

¹ H NMR δ0.26, 0.48, 0.67, 0.81, 1.6, 1.8, 2.5, 2.7, 2.9, 3.48, 5.14,5.86, 6.81, 7.0-7.5, 9.46.

EI HRMS m/z=523.2350.

TLC R_(f) 0.27 (5% ethyl acetate in dichloromethane.)

PREPARATION 54

3-(α-Cyclopropyl-meta-aminobenzyl)-6-(α-ethyl-phenethyl)-4-hydroxy-2H-pyran-2-one(Formula L-5) Refer to Chart L

A mixture of 146 mg of the title compound of Preparation 53 and 50 mg of5% palladium on carbon in 2 ml of methanol is shaken under 40 psi ofhydrogen for two hours, then filtered through Celite. The filtrate isconcentrated under reduced pressure to give 105 mg (96%) of the titlecompound.

Physical characteristics are as follows:

¹ H NMR δ0.25, 0.5, 0.65, 0.81, 1.6, 2.5, 2.7, 2.9, 3.4, 5.79, 6.5,6.8-7.3.

TLC R_(f) 0.38 (30% ethyl acetate in dichloromethane).

EXAMPLES 136-150

Utilizing procedures analogous to those described above, and reactingthe compound of formula L-5 with the appropriate sulfonyl chloride, thefollowing additional compounds of the present invention are prepared.Individual stereoisomers are prepared by chiral HPLC resolution ofintermediates such as the compounds of formulas L-3, L-4, L-5 and L-6.(Refer to Chart L).

136) N-(3-{Cyclopropyl-6-(1-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.29 (5% methanol in dichloromethane)

¹ H NMR δ0.2, 0.5, 0.65, 0.86, 1.63, 1.80, 2.51, 2.8, 3.3, 3.62, 5.7,6.8-7.4 ppm.

HRMS: 533.1998

137) N-(3-(R or S)-{Cyclopropyl-6-(1-(R)-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.32 (5% methanol in dichloromethane)

¹ H NMR δ0.18, 0.43, 0.63, 0.83, 1.6, 1.75, 2.5, 2.7-2.9, 3.3, 3.55,5.76, 6.9-7.4 ppm.

HRMS: 533.1983

138) N-(3-(R or S)-{Cyclopropyl-6-(1-(R)-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.30 (5% methanol in dichloromethane)

¹ H NMR δ0.2, 0.5, 0.65, 0.86, 1.63, 1.80, 2.51, 2.8, 3.3, 3.62, 5.7,6.8-7.4 ppm.

HRMS: 533.1993

139) N-(3-(R or S)-{Cyclopropyl-6-(1-(S)-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.30 (5% methanol in dichloromethane)

¹ H NMR δ0.2, 0.5, 0.65, 0.86, 1.63, 1.80, 2.51, 2.8, 3.3, 3.62, 5.7,6.8-7.4 ppm.

HRMS: 533.1993

140) N-(3-(R or S)-{Cyclopropyl-6-(1-(S)-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.30 (5% methanol in dichloromethane)

¹ H NMR δ0.17, 0.44, 0.62, 0.83, 1.6, 1.75, 2.50, 2.7-3.0, 3.3, 3.53,5.80, 6.9-7.4 ppm.

HRMS: 533.1990

141) N-(3-(R or S)-{Cyclopropyl-6-(1-(R)-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-pyridinesulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.34 (30% ethyl acetate in dichloromethane)

¹ H NMR δ0.2, 0.45, 0.6, 0.86, 1.5-1.9, 2.5, 2.8-3.0, 3.2, 5.7, 6.9-7.4,7.8, 8.6 ppm.

MS: 530

142) N-(3-(R or S)-{Cyclopropyl-6-(1-(R)-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-pyridinesulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.35 (30% ethyl acetate in dichloromethane)

¹ H NMR δ0.11, 0.20, 0.43, 0.58, 0.85, 1.5-1.8, 2.5, 2.7-3.0, 3.3, 5.69,6.9-7.4, 7.8, 8.6 ppm.

MS: 530

143) N-(3-(R or S)-{Cyclopropyl-6-(1-(R)-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-2-sulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.34 (5% methanol in dichloromethane)

¹ H NMR δ0.19, 0.5, 0.65, 0.89, 1.6-1.9, 2.5, 2.8-3.0, 3.3, 3.40, 5.70,6.8-7.4 ppm.

MS: 533

144) N-(3-(R or S)-{Cyclopropyl-6-(1-(R)-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-2-sulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.34 (5% methanol in dichloromethane)

¹ H NMR δ0.20, 0.44, 0.65, 0.88, 1.6-1.8, 2.5, 2.8-3.0, 3.3, 3.42, 5.73,6.8-7.4 ppm.

MS: 533

145) N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-2-sulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.22 (5% methanol in dichloromethane)

¹ H NMR δ0.16, 0.24, 0.47, 0.64, 0.86, 1.2-1.9, 3.2-3.4, 3.47, 3.7-4.0,5.89, 6.9-7.4 ppm.

MS: 541

145A) N-(3- Cyclopropyl 4-hydroxy-2-oxo-6- 1-(tetrahydro-2H-pyran-3-yl)methyl!propyl!-2H-pyran-3-yl!methyl!phenyl!-8-quinolinesulfonamide

Physical characteristics are as follows:

MW Found: m/z 588.

145B) N-(3- Cyclopropyl 4-hydroxy-2-oxo-6- 1-(tetrahydro-2H-pyran-3-yl)methyl!propyl!-2H-pyran-3-yl!methyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide

Physical characteristics are as follows:

MW Found: m/z 541.

146) N-(3-{Cyclopropyl-6-(1-(R)-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-benzimidazole-2-sulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.40 (50% ethyl acetate in dichloromethane)

¹ H NMR δ0.1-0.6, 0.85, 1.5-1.7, 2.5, 2.7-3.0, 3.3, 5.74, 6.7-7.3,7.5-7.7 ppm.

HRMS: 570.2054

147) N-(3-{Cyclopropyl-6-(1-(R)-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1H-imidazole-2-sulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.31 (5% methanol in dichloromethane)

¹ H NMR δ0.2, 0.4, 0.6, 0.87, 1.5-1.8, 2.5, 2.8-3.0, 3.3, 5.54, 6.8,6.9-7.4 ppm.

148) N-(3-(R or S)-{Cyclopropyl-6-(1-(R)-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-4-cyanobenzenesulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.47 (20% ethyl acetate in dichloromethane)

¹ H NMR δ0.1, 0.2, 0.4, 0.6, 0.84, 1.5-1.8, 2.5, 2.7-3.0, 3.3, 5.70,6.9, 7.0-7.3, 7.6, 7.8 ppm.

HRMS: 554.1886

149) N-(3-(R or S)-{Cyclopropyl-6-(1-(R)-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-4-cyanobenzenesulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.35 (15% ethyl acetate in dichloromethane)

¹ H NMR δ0.1, 0.2, 0.4, 0.6, 0.85, 1.5-1.9, 2.5, 2.7-3.0, 3.3, 5.7,6.9-7.3, 7.6, 7.8 ppm.

HRMS: 554.1876

150) N-(3-{Cyclopropyl-6-(1-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-4-nitrobenzenesulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.28 (10% ethyl acetate in dichloromethane)

¹ H NMR δ0.1, 0.2, 0.4, 0.6, 0.83, 1.5-1.9, 2.5, 2.7-3.0, 3.3, 5.70,6.9-7.3, 7.9, 8.2 ppm.

HRMS: 574.1773

PREPARATION 55

(2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy)-p-toluenesulfonate (Formula M-2)Refer to Chart M

To a stirred suspension of 19.1 g of p-toluenesulfonyl chloride in 100ml of dichloromethane is added a mixture of 16 ml of triethylene glycolmonomethyl ether and 10 ml of pyridine, followed by 200 mg ofdimethylaminopyridine. After three days the mixture is concentratedunder reduced pressure, and the residue partitioned between ethylacetate and dilute aqueous hydrochloric acid. The organic phase iswashed with water, aqueous sodium bicarbonate, and brine, and dried overmagnesium sulfate. After removal of solvent under reduced pressure, theresidue is flash chromatographed on silica using 25% ethyl acetate indichloromethane to afford 18.25 g of the title compound as a colorlessliquid.

Physical characteristics are as follows:

TLC R_(f) 0.27 (20% ethyl acetate in dichloromethane)

¹ H NMR δ2.45, 3.38, 3.5-3.8, 4.15, 7.35, 7.8 ppm.

IR 2879, 1357, 1190, 1177, 1108, 1099, 924, 665 cm⁻¹

MS: 318

PREPARATION 56

2-Hydroxy-4-(2-(2-(2-methoxyethoxy)-ethoxy)-ethoxy)-acetophenone(Formula M-3) Refer to Chart M

A mixture of 1.52 g of 2,4-dihydroxyacetophenone, 3.82 g of the tosylateof Preparation 55, 3.26 g of cesium carbonate, and 0.2 g of potassiumiodide in 20 ml of dioxane is heated overnight at 100°, then cooled andpartitioned between dichloromethane and dilute aqueous hydrochloricacid. The aqueous phase is extracted with two additional portions ofdichloromethane, and the combined organic phase dried over magnesiumsulfate and then concentrated under reduced pressure. Flashchromatography of the residue on silica gel using 80-100% ethyl acetatein hexane provides 2.91 g of the title compound as a nearly colorlessliquid.

Physical characteristics are as follows:

TLC R_(f) 0.35 (80% ethyl acetate in hexane)

¹ H NMR δ2.56, 3.38, 3.5-3.9, 4.2, 6.4-6.5, 7.6 ppm.

IR 1635, 1372, 1257, 1133 cm⁻¹

MS: 298

PREPARATION 57

3-(2-Hydroxy-4-(2-(2-(2-methoxyethoxy)-ethoxy)-ethoxy)-phenyl-3-oxopropionicacid ethyl ester (Formula M-4) Refer to Chart M

To a stirred solution of 1.49 g of the title compound of Preparation 56in 10 ml of diethyl carbonate is added, in portions, 600 mg of 60%sodium hydride dispersion in mineral oil. The resulting mixture isheated at 80° for two hours, then cooled and partitioned betweendichloromethane and dilute aqueous hydrochloric acid. The organic phaseis dried over magnesium sulfate and concentrated under reduced pressure,and the residue purified by flash chromatography on silica gel using20-30% ethyl acetate in dichloromethane to afford 0.91 g of the titlecompound as a yellow oil.

Physical characteristics are as follows:

TLC R_(f) 0.44 (3% acetic acid and 30% ethyl acetate in dichloromethane)

¹ H NMR δ1.3, 3.38, 3.5-4.0, 4.2, 6.4-6.5, 7.6 ppm.

MS: 370

PREPARATION 58

4-Hydroxy-(2-(2-(2-methoxyethoxy)-ethoxy)-ethoxy)-coumarin (Formula M-5)Refer to Chart M

A solution of 789 mg of the title compound of Preparation 57 in 10 ml ofacetic acid is refluxed for two hours, then concentrated under reducedpressure. Flash chromatography of the residue on silica using 5-10%acetic acid in ethyl acetate provides 634 mg of the title compound as abuff colored solid.

Physical characteristics are as follows:

TLC R_(f) 0.31 (10% acetic acid in ethyl acetate)

¹ H NMR δ3.37, 3.5-3.9, 4.1, 5.67, 6.6, 6.7, 7.6 ppm.

MS: 324

PREPARATION 59

3- (3-Benzyloxycarbonylaminophenyl)-cyclopropylmethyl!-4-hydroxy-7-{2-2-(2-methoxyethoxy)-ethoxy!-ethoxy}-coumarin (Formula M-6) Refer toChart M

A mixture of 704 mg of the title compound of Preparation 58, 775 mg ofmeta-benzyloxycarbonylaminophenyl cyclopropyl carbinol of formula F-5,and 62 mg of p-toluenesulfonic acid monohydrate in 8 ml ofdichloromethane is refluxed for 18 hours through ca. 10 ml of 3 Åsieves. The solution is then concentrated under reduced pressure and theresidue flash chromatographed on silica gel using 10-20% of (10% aceticacid in ethyl acetate) in dichloromethane to afford 760 mg of the titlecompound.

Physical characteristics are as follows:

TLC R_(f) 0.33 (2% acetic acid and 20% ethyl acetate in dichloromethane)

¹ H NMR δ0.27, 0.46, 0.71, 1.61, 3.33, 3.5-3.9, 4.1, 5.13, 6.6, 6.7,7.1-7.6 ppm.

PREPARATION 60

3- (3-Aminophenyl)-cyclopropylmethyl!-4-hydroxy-7-{2-2-(2-methoxyethoxy)-ethoxy!-ethoxy}-coumarin (Formula M-7) Refer toChart M

A solution of 760 mg of the title compound of Preparation 59, 800 mg ofammonium formate, and 200 mg of 5% palladium on charcoal catalyst in 8ml of methanol is stirred under argon for one hour, then filteredthrough a pad of diatomaceous earth. The filtrate is concentrated underreduced pressure and the residue triturated with dichloromethane.Removal of solvent under reduced pressure provides 591 mg of the titleamine.

Physical characteristics are as follows:

TLC R_(f) 0.29 (5% methanol in dichloromethane)

EXAMPLE 151

N-(3-{Cyclopropyl-7-(2-(2-(2-methoxyethoxy)-ethoxy)ethoxy)-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula M-8) Refer to Chart M

To a stirred solution of 70 mg of the title compound of Preparation 60and 24 μL of pyridine in 0.5 ml of dichloromethane is added 27 mg of1-methylimidazole-4-sulfonyl chloride. After 18 hours, the solution isflash chromatographed on silica gel using 5-15% methanol indichloromethane, affording 76 mg of the title sulfonamide as a pinkamorphous foam.

Physical characteristics are as follows:

TLC R_(f) 0.21 (5% methanol in dichloromethane)

¹ H NMR δ0.16, 0.29, 0.45, 0.61, 1.71, 3.34, 3.4-3.9, 4.1, 6.6-6.8,7.0-7.4, 7.7 ppm.

HRMS: 614.2179

EXAMPLES 152-154

Utilizing procedures analogous to those described above, the followingadditional compounds of the present invention are prepared:

152) N-(3-{Cyclopropyl-7-methoxy-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-1-methyl-1H-imidazole-4-sulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.29 (5% methanol in dichloromethane)

¹ H NMR δ0.18, 0.35, 0.50, 0.63, 1.61, 3.51, 3.7, 3.84, 6.7-6.8,7.1-7.4, 7.7 ppm.

HRMS: 481.1301

153) N-(3-{Cyclopropyl-7-(2-(2-(2-methoxyethoxy)-ethoxy)ethoxy)-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-8-quinolinesulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.41 (5% methanol in dichloromethane)

¹ H NMR δ-0.03, 0.31, 0.47, 1.30, 3.36, 3.5-3.8, 3.9, 4.2, 6.6-7.6, 7.8,8.0, 8.2 ppm.

HRMS: 661.2219

154) N-(3-{Cyclopropyl-7-(2-(2-(2-methoxyethoxy)-ethoxy)ethoxy)-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-2-pyridinesulfonamide

Physical characteristics are as follows:

TLC R_(f) 0.31 (5% methanol in dichloromethane)

¹ H NMR δ0.13, 0.34, 0.49, 0.63, 1.6, 3.36, 3.5-3.9, 4.1, 6.68, 6.8,7.1-7.4, 7.6-7.8, 8.5 ppm.

HRMS: 611.2051

EXAMPLES 155-190

The following additional compounds of the present invention are preparedby procedures analogous to those described above:

155) N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-pyridinesulfonamide

156) N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-4-cyano-2-pyridinesulfonamide

157) N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-quinolinesulfonamide

158) N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-hydroxybenzenesulfonamide

159) N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-pyrazolesulfonamide

160) N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-quinazolinesulfonamide

161) N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-7H-purine-6-sulfonamide

162) N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1H-imidazole-2-sulfonamide

163) N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-benzimidazole-2-sulfonamide

164) N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-thiazole-4-sulfonamide

165) N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-4-ethoxycarbonyl-1H-imidazole-2-sulfaonamide

166) N-(3-{Cyclopropyl-6-(1-(tetrahydropyran-4-ylmethyl)-propyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-3-hydroxy-2-pyridinesulfonamide

167) N-(3-{Cyclopropyl-6-(1-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-pyridinesulfonamide

168) N-(3-{Cyclopropyl-6-(1-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-4-cyano-2-pyridinesulfonamide

169) N-(3-{Cyclopropyl-6-(1-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-quinolinesulfonamide

170) N-(3-{Cyclopropyl-6-(1-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-hydroxybenzenesulfonamide

171) N-(3-{Cyclopropyl-6-(1-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-pyrazolesulfonamide

172) N-(3-{Cyclopropyl-6-(1-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-2-quinazolinesulfonamide

173) N-(3-{Cyclopropyl-6-(1-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-7H-purine-6-sulfonamide

174) N-(3-{Cyclopropyl-6-(1-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-1H-imidazole-2-sulfonamide

175) N-(3-{Cyclopropyl-6-(1-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-benzimidazole-2-sulfonamide

176) N-(3-{Cyclopropyl-6-(1-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-thiazole-4-sulfonamide

177) N-(3-{Cyclopropyl-6-(1-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-4-ethoxycarbonyl-1H-imidazole-2-sulfaonamide

178) N-(3-{Cyclopropyl-6-(1-ethylphenethyl)-4-hydroxy-2-oxo-2H-pyran-3-yl!-methyl}-phenyl)-3-hydroxy-2-pyridinesulfonamide

179) N-(3-{Cyclopropyl-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-2-pyridinesulfonamide

180) N-(3-{Cyclopropyl-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-4-cyano-2-pyridinesulfonamide

181) N-(3-{Cyclopropyl-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-2-quinolinesulfonamide

182) N-(3-{Cyclopropyl-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-2-hydroxybenzenesulfonamide

183) N-(3-{Cyclopropyl-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-2-pyrazolesulfonamide

184) N-(3-{Cyclopropyl-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-2-quinazolinesulfonamide

185) N-(3-{Cyclopropyl-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-7H-purine-6-sulfonamide

186) N-(3-{Cyclopropyl-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-1H-imidazole-2-sulfonamide

187) N-(3-{Cyclopropyl-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-benzimidazole-2-sulfonamide

188) N-(3-{Cyclopropyl-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-thiazole-4-sulfonamide

189) N-(3-{Cyclopropyl-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-4-ethoxycarbonyl-1H-imidazole-2-sulfaonamide

190) N-(3-{Cyclopropyl-4-hydroxycoumarin-3-yl!-methyl}-phenyl)-3-hydroxy-2-pyridinesulfonamide

PREPARATION 61

Cyclopropyl-(3-nitrophenyl)methanone (Formula N-2) Refer to Chart N

Charge a jacketed 1 L three neck round bottom flask equipped withstirrer and addition funnel under nitrogen with 580 mL fuming nitricacid and cool to -40° C. Slowly, over 1.5 hours, add cyclopropyl phenylketone of formula N-1 (100 g) keeping the temperature below -35° C. Stir3 hours, monitoring reaction by TLC. Pour reaction mixture into 3 kgice/water. Extract with 3×500 mL ethyl acetate. Wash combined organicphase with 2×1.5 L saturated aqueous sodium bicarbonate, dry overmagnesium sulfate, filter and concentrate to 138 g. Dissolve residue in270 mL methanol, cool to -20° C. for 18 hours, filter and wash cake withcold methanol. Dry product under reduced pressure for 72 hours,obtaining 63.86 g. GC analysis (15 m. DB-1, T_(o) =100° C., 10° C./min.,RT -6.0 min.) indicates material to be >98% pure.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ8.86, 8.43, 8.34, 7.70, 2.72, 1.33, 1.17 ppm.

IR (Nujol) 2954, 2925, 1664, 1614, 1529, 1442, 1386, 1352, 1225, 1082,1047, 852, 720, 689 cm⁻¹.

Elemental analysis, Found: C, 62.89; H, 4.73; N, 7.32.

MS (EI) 191, 150, 104, 69 m/z.

PREPARATION 62

Cyclopropyl-(3-aminophenyl)methanone (Formula N-3) Refer to Chart N

Charge platinum on carbon (8.7 g) to Paar bottle. Charge a flask withcyclopropyl(3-nitrophenyl)methanone of Preparation 61 (86.7 g) andmethanol (1.56 L) and warm to dissolve, then cool with ice bath to 9° C.Hydrogenate for 50 minutes, keeping temperature below 35° C. andmonitoring reaction by TLC. Filter reaction mixture through solka floc,and concentrate under reduced pressure to 70 g.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.99, 7.47-7.19, 6.84, 3.84, 2.60, 1.23-1.15, 1.03-0.96ppm.

¹³ C NMR (CDCl₃) δ200.9, 146.8, 139.1, 129.4, 119.3, 118.4, 113.9, 17.2,11.6 ppm.

PREPARATION 63

Cyclopropyl-(3-aminocarbobenzoxyphenyl)methanone (Formula N-4) Refer toChart N

Charge a 3 L round bottom flask equipped with mechanical stirrer andaddition funnel under nitrogen with cyclopropyl-(3-aminophenyl)methanoneof Preparation 62 (70.0 g), diisopropylethylamine (DIPEA, 90.2 mL) andmethylene chloride (CH₂ Cl₂) (1.3 L). Cool reaction mixture to 0° C.Dilute the benzylchloroformate (67.5 mL) with methylene chloride (186mL) and add to the substrate solution over one hour keeping temperatureat 0°-5° C. A heavy precipitate will form. Allow to warm with stirringfor 1.5 hours monitoring reaction by TLC. Pour reaction mixture into 600mL 1N HCl/600 g ice/4.2 L methylene chloride and stir to dissolve.Separate phases and dry organic phase over magnesium sulfate, filter andconcentrate to a dryness. Slurry solids in 3 mL/g hexane, filter, andvacuum dry for 125 g.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ8.01, 7.76-7.69, 7.43-7.33, 7.18, 5.21, 2.64,1.25-1.20, 1.03-0.97 ppm.

¹³ C NMR (CDCl₃) δ200.6, 153.4, 138.7, 138.5, 135.9, 129.3, 128.6,128.4, 123.1, 122.8, 118.1, 67.2, 17.3, 12.0 ppm.

PREPARATION 64

Cyclopropyl-(3-aminocarbobenzoxyphenyl)methanol (Formula N-5) Refer toChart N

Charge a 2 L three neck round bottom flask equipped with overheadstirrer under nitrogen withcyclopropyl-(3-aminocarbobenzoxyphenyl)methanone of Preparation 63 (25g), tetrahydrofuran (THF) (450 mL) and ethanol (90 mL). Cool reactionmixture to 0°-5° C. and add the sodium borohydride pellets (12.4 g) inthree equal portions over 30 minutes. Allow to warm to 23° C. and stirfor 20 hours, monitoring reaction by TLC. Recool reaction mixture to0°-5° C. and slowly quench by adding 90 mL 1N hydrochloric acid, keepingthe temperature below 10° C. Pour with stirring into methylene chloride(600 mL) and 1N hydrochloric acid (400 mL). Separate the phases and washthe organic phase with saturated sodium chloride solution (1 L). Dryover magnesium sulfate, filter, and concentrate to 23.7 g.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.41-7.35, 7.33, 7.17, 7.10, 5.17, 3.93, 2.36,1.16-1.12, 0.60-0.32 ppm.

¹³ C NMR (CDCl₃) δ153.5, 145.0, 137.9, 136.1, 129.0, 128.6, 128.3,121.2, 117.9, 116.5, 67.9, 67.0, 19.1, 3.6, 2.8 ppm.

PREPARATION 65

Carbamic acid, 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-, phenylmethyl ester (Formula N-6) Refer toChart N

A 12-L, three-necked, round-bottomed flask with a Soxhlet extractorcontaining 3 Å molecular sieves (180 g) and nitrogen inlet is chargedwith cyclooctene-1-acrylic acid, β, 2-dihydroxy-δ-lactone (59.6 g),p-toluenesulfonic acid (14.9 g), and methylene chloride (7.2 L). Thetitle compound of Preparation 64 (90.0 g) is added, and the reactionmixture is warmed to reflux for 1 h. The reaction mixture is then cooledto 20° C. and washed with 1:1 saturated sodium chloride/saturated sodiumbicarbonate (3 L), water (3 L), and saturated sodium chloride (3 L),backwashing each aqueous phase with methylene chloride (2×1.5 L). Theorganic layers are then combined, dried over magnesium sulfate, filteredand concentrated to ca. 1.5 L. The reaction mixture is cooled to -20° C.for 72 h, filtered, and dried under reduced pressure to give 103.5 g.The crude product is then slurried with 12.5 mL/g of hexane, filtered,and dried to give 102.4 g of the title compound. An additional 10.9 g ofthe title compound is obtained by concentrating the mother liquors fromthe crystallization and recrystallizing the residue from ethyl acetate.

Physical characteristics are as follows:

MP 113°-115° C. (decomposition).

¹ H NMR (CDCl₃) δ7.48, 7.38-7.26, 7.17, 6.70, 6.29, 5.20, 3.95,2.64-2.60, 2.47-2.43, 1.76-1.72, 1.61-1.42, 0.88, 0.73-0.72, 0.63-0.55,0.29-0.26 ppm.

¹³ C NMR (CDCl₃) δ165.6, 164.0, 161.3, 142.2, 138.5, 129.9, 128.5,128.3, 128.2, 122.9, 118.0, 117.9, 117.6, 110.7, 106.0, 67.0, 43.7,30.7, 29.1, 28.8, 26.2, 25.8, 22.1, 13.0, 4.9, 3.8 ppm.

IR (Nujol) 3304, 2995, 2953, 2923, 2855, 1734, 1698, 1665, 1666, 1633,1610, 1595, 1553, 1491, 1463, 1455, 1445, 1406, 1377, 1313, 1222, 1175,1085, 1068, 740, 696 cm⁻¹.

MS (EI) m/z 473, 445, 382, 338, 91.

For high resolution, Found: 473.2202.

PREPARATION 66

3-(3-Aminophenyl)cyclopropylmethyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one (Formula N-7) Refer to Chart N

In a 100-mL, three-necked, round-bottomed flask with a reflux condensorand nitrogen inlet, 10% palladium on carbon (1.0 g) is added to amixture of the title product of formula N-6, prepared in Preparation 65(1.95 g) in cyclohexene (50 mL) and the mixture is refluxed for 4 h. Themixture is then filtered through Celite, washed with methylene chloride(CH₂ Cl₂), and concentrated to give 1.25 g of the title compound as awhite solid.

Physical characteristics are as follows:

MP 75°-79° C.

IR (Nujol) 2995, 2951, 2921, 2868, 1660, 1619, 1605, 1590, 1551, 1491,1460, 1447, 1428, 1404, 1247, 1226, 1202, 1191, 1172, 1126 cm⁻¹.

MS (EI) m/z 339, 310, 213, 187, 159.

¹ H NMR (CDCl₃) δ7.16, 6.96, 6.84, 6.63, 5.67, 3.87, 2.61, 2.48-2.37,1.98, 1.75, 1.63-1.26, 0.74-0.65, 0.61-0.53, 0.28-0.22 ppm.

¹³ C NMR (CDCl₃) δ164.2, 161.1, 142.8, 130.2, 117.7, 117.6, 114.7,114.6, 114.5, 110.9, 106.2, 43.5, 30.6, 29.1, 28.8, 26.2, 25.8, 22.0,12.8, 4.7, 3.7 ppm.

For high resolution, Found: 339.1845.

PREPARATION 67

4-Cyano-N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-benzenesulfonamide (Formula O-3 wherein R₆₁is 4-cyanophenyl) Refer to Chart O

A solution of the title product of Preparation 66 (660 mg), pyridine(320 μL), and 4-cyanobenzenesulfonyl chloride (440 mg) indichloromethane (40 mL) is stirred at room temperature for 18 hr. Thecrude reaction mixture is evaporated to a volume of 5 ml andchromatographed on silica gel using 50% ethyl acetate in hexane aseluent to give the title compound (641 mg) as a white amorphous solid.This amorphous solid is alternatively crystallized from acetone:hexaneto give 499 mg.

Physical characteristics are as follows:

White solid mp: 183°-183.5° C.

Elemental analysis: found, C, 66.76; H, 5.68; N, 5.38; s, 6.30.

MS(EI): 504, 476, 463, 338, 309, 233, 220, 207, 195, 186, 153, 144, 130,117, 102.

HRMS: 504.1710.

TLC(silica gel GF): R_(f) =0.4 in 50% ethyl acetate in hexane.

EXAMPLE 191

Disodium-4-cyano-N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-benzenesulfonamide

To 12.6 g of the title product of Preparation 67 is added 500 ml ofmethanol and, with rapid stirring, 50 ml of a 1N aqueous NaOH solution.The reaction solution is allowed to stir at room temperature for 1 hour.The yellow solution is evaporated to dryness at 35° C. and the resultingamorphous residue is dissolved in absolute ethanol and re-evaporated todryness. The yellow residue is kept under high vacuum at roomtemperature for 18 hours to yield 14 g of a yellow amorphous solid.

Physical characteristics are as follows:

TLC(silica gel GF): R_(f) =0.8 streak from the origin (20% ethylacetatein methylene chloride)

K.F. Water: 6.16%

Melt Solvate: 4.2% ethanol

Weight Loss at Room Temperature: 4.99%

Ash: found: 7.83%; Calc'd: 7.50% (corrected for 6.16% water and 4.2%ethanol)

PREPARATION 68

N-methyl-3(3-aminophenyl)cyclopropylmethyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one

To 678 mg of the title product of Preparation 66 is added 100 ml ofabsolute ethanol and 330 mg of 10% Pd/C. 183 microliters of a 35% CH₂O/H₂ O solution is added and the mixture allowed to shake on a Paarapparatus, under 50 lbs of hydrogen, for 2 hours at room temperature.The reaction is filtered over celite and the filter cake is washed wellwith ethanol. The resulting amber solution is evaporated to dryness. Theresulting residue is chromatographed using 10% ethyl acetate inmethylene chloride to give 110 mg of the title product. This material isused without further purification in the synthesis of the followingsulfonamides.

Physical characteristics are as follows:

TLC(silica gel GF): R_(f) =0.5 in 10% ethyl acetate in methylenechloride.

¹ H NMR (CDCl₃) δ7.19, 6.90, 6.71, 6.54-6.52, 3.90, 2.80, 2.63-2.59,2.43-2.39, 1.75-1.26, 0.70-0.53, 0.28-0.22 ppm.

EXAMPLE 192

4-Cyano-N-methyl-N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-benzenesulfonamide

A solution of the title compound of Preparation 68 (35 mg), pyridine (16μL), and 4-cyanobenzenesulfonyl chloride (20.1 mg) in dichloromethane (2mL) is stirred at room temperature for 18 hr. The crude reaction mixtureis chromatographed on silica gel using 10% ethyl acetate in methylenechloride as eluent to give 27 mg of the title compound as a whiteamorphous solid.

Physical characteristics are as follows:

MS(EI): 518, 490, 352, 233, 207, 172, 158, 143, 129, 115, 102, 81, 54,43.

TLC(silica gel GF): R_(f) =0.7 in 10% ethyl acetate in methylenechloride.

¹ H NMR (CDCl₃) δ7.75-7.72, 7.63-7.60, 7.38-7.19, 6.97-6.94, 6.62, 3.86,3.19, 2.66-2.62, 2.54-2.50, 1.76-1.20, 0.70-0.59, 0.47-42, 0.24-0.19ppm.

EXAMPLE 193

4-Fluoro-N-methyl-N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-benzenesulfonamide

A solution of the title compound of Preparation 68 (20 mg), pyridine (11μL), and 4-fluorobenzenesulfonyl chloride (10.7 mg) in dichloromethane(2 mL) is stirred at room temperature for 18 hr. The crude reactionmixture is chromatographed on silica gel using 10% ethyl acetate inmethylene chloride as eluent to give 19 mg of the title compound as awhite amorphous solid.

Physical characteristics are as follows:

MS(EI): 512, 483, 470, 366, 352, 324, 247, 227, 207, 172, 158, 147, 118,55.

HRMS: Found: 512.1915

TLC(silica gel GF): R_(f) =0.7 in 10% ethyl acetate in methylenechloride.

¹ H NMR (CDCl₃) δ7.53-7.48, 7.33-7.23, 7.13-7.07, 6.99-6.97, 6.38, 3.93,3.16, 2.63-2.61, 2.49-2.46, 1.76-1.25, 0.78-0.61, 0.51-0.45, 0.30-0.17ppm.

EXAMPLE 194

N-methyl-N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-benzenesulfonamide

A solution of the title compound of Preparation 68 (33.4 mg), pyridine(16 μL), and benzenesulfonyl chloride (16.6 mg) in dichloromethane (2mL) is stirred at room temperature for 18 hr. The crude reaction mixturewas chromatographed on silica gel using 10% ethyl acetate in methylenechloride as eluent to give 20 mg of the title compound as a whiteamorphous solid.

Physical characteristics are as follows:

TLC(silica gel GF): R_(f) =0.7 in 10% ethyl acetate in methylenechloride.

¹ H NMR (CDCl₃) δ7.59-7.41, 7.33-7.23, 6.98-6.96, 6.44, 3.90, 3.16,2.64-2.60, 2.50-2.48, 1.75-1.20, 0.67-0.40, 0.23-0.20 ppm.

EXAMPLE 195

N-methyl-N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-1H-Imidazole-1-methyl-sulfonamide

A solution of the title compound of Preparation 68 (33.4 mg), pyridine(16 μL), and N-methyl-imidazole-3-sulfonyl chloride (16 mg) indichloromethane (2 mL) is stirred at room temperature for 18 hr. Thecrude reaction mixture is chromatographed on silica gel using 50% ethylacetate in methylene chloride as eluent to give 28 mg of the titlecompound as a white amorphous solid.

Physical characteristics are as follows:

TLC(silica gel GF): R_(f) =0.5 in 50% ethyl acetate in methylenechloride.

¹ H NMR (CDCl₃) δ7.43, 7.33, 7.27-7.15, 3.84-3.81, 3.69, 3.35,2.63-2.59, 2.50-2.46, 1.75-1.26, 0.68, 0.55, 0.47-0.42, 0.24-0.20 ppm.

Utilizing procedures analogous to those described above, the followingcompounds of the present invention are prepared:

196) 5-cyano-N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-2-pyridinesulfonamide

197) N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-2-quinolinesulfonamide

198) N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-2-imidazolesulfonamide

199) N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-2-pyrimidinesulfonamide

200) N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-2-benzimidazolesulfonamide

201) N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-2-quinazolinesulfonamide

202) N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-6-purinesulfonamide

203) 5-cyano-N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-N-methyl-2-pyridinesulfonamide

204) N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-N-methyl-2-quinolinesulfonamide

205) N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-N-methyl-2-imidazolesulfonamide

206) N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-N-methyl-2-pyrimidinesulfonamide

207) N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-2-benzimidazolesulfonamide

208) N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-2-quinazolinesulfonamide

209) N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-N-methyl-6-purinesulfonamide

210) N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-N-methyl-4-thiazolesulfonamide

211) N- 3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-N-methyl-2-pyridinesulfonamide

212) 5-cyano-N-6-(1'-benzylpropyl)-4-hydroxy-3-(1'-cyclopropylmethylphenyl)-2-pyrone!-N-methyl-2-pyridinesulfonamide

213) N-6-(1'-benzylpropyl)-4-hydroxy-3-(1'-cyclopropylmethylphenyl)-2-pyrone!-N-methyl-2-quinolinesulfonamide

214) N-6-(1'-benzylpropyl)-4-hydroxy-3-(1'-cyclopropylmethylphenyl)-2-pyrone!-N-methyl-2-imidazolesulfonamide

215) N-6-(1'-benzylpropyl)-4-hydroxy-3-(1'-cyclopropylmethylphenyl)-2-pyrone!-N-methyl-2-pyrimidinesulfonamide

216) N-6-(1'-benzylpropyl)-4-hydroxy-3-(1'-cyclopropylmethylphenyl)-2-pyrone!-N-methyl-2-benzimidazolesulfonamide

217) N-6-(1'-benzylpropyl)-4-hydroxy-3-(1'-cyclopropylmethylphenyl)-2-pyrone!-N-methyl-2-quinazolinesulfonamide

218) N-6-(1'-benzylpropyl)-4-hydroxy-3-(1'-cyclopropylmethylphenyl)-2-pyrone!-N-methyl-6-purinesulfonamide

219) N-6-(1'-benzylpropyl)-4-hydroxy-3-(1'-cyclopropylmethylphenyl)-2-pyrone!-N-methyl-4-thiazolesulfonamide

220) N-6-(1'-benzylpropyl)-4-hydroxy-3-(1'-cyclopropylmethylphenyl)-2-pyrone!-N-methyl-2-pyridinesulfonamide

221) 5-cyano-N-3-(1'-cyclopropylmethylphenyl)-4-hydroxycoumarin!-N-methyl-2-pyridinesulfonamide

222) N-3-(1'-cyclopropylmethylphenyl)-4-hydroxycoumarin!-N-methyl-2-quinolinesulfonamide

223) N-3-(1'-cyclopropylmethylphenyl)-4-hydroxycoumarin!-N-methyl-2-imidazolesulfonamide

224) N-3-(1'-cyclopropylmethylphenyl)-4-hydroxycoumarin!-N-methyl-2-pyrimidinesulfonamide

225) N-3-(1'-cyclopropylmethylphenyl)-4-hydroxycoumarin!-N-methyl-2-benzimidazolesulfonamide

226) N-3-(1'-cyclopropylmethylphenyl)-4-hydroxycoumarin!-N-methyl-2-quinazolinesulfonamide

227) N-3-(1'-cyclopropylmethylphenyl)-4-hydroxycoumarin!-N-methyl-6-purinesulfonamide

228) N-3-(1'-cyclopropylmethylphenyl)-4-hydroxycoumarin!-N-methyl-4-thiazolesulfonamide

229) N-3-(1'-cyclopropylmethylphenyl)-4-hydroxycoumarin!-N-methyl-2-pyridinesulfonamide

230) 5-cyano-N- 3-1-(4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-N-methyl-2-pyridinesulfonamide

231) N- 3-1-(4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-N-methyl-2-quinolinesulfonamide

232) N- 3-1-(4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-N-methyl-2-imidazolesulfonamide

233) N- 3-1-(4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-N-methyl-2-pyrimidinesulfonamide

234) N- 3-1-(4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-N-methyl-2-benzimidazolesulfonamide

235) N- 3-1-(4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-N-methyl-2-quinazolinesulfonamide

236) N- 3-1-(4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-N-methyl-6-purinesulfonamide

237) N- 3-1-(4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-N-methyl-4-thiazolesulfonamide

238) N- 3-1-(4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl)-propyl!-phenyl!-N-methyl-2-pyridinesulfonamide

EXAMPLE 239

2-Pyridylsulfonamide, N- 4-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-(Formula P-2, R is 2-pyridyl) Refer to ChartP

3-(3-Aminophenyl)cyclopropylmethyl!-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cyclooctab!pyran-2-one of Preparation 66 (100 mg) is dissolved in methylenechloride (3 mL) and pyridine (70 μL) added. 2-Pyridylsulfonyl chloride(52 mg) is added and the solution stirred for 2 hr at 25° C. Chloroform(25 mL) is added and the combined extracts washed with 1N.HCl (20 mL)and dried over sodium sulfate. Removal of the solvent gives a pink gumwhich is chromatographed over silica gel using the flash columntechnique eluting with 60% ethyl acetate-hexane. The title compound isobtained as a white solid (80 mg).

Physical characteristics are as follows:

MS m/z 480, 339, 338, 186, 145, 144, 132, 130, 78, 55.

EXAMPLE 240

4-Pyridylsulfonamide, N- 4-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-(Formula P-2, R is 4-pyridyl) Refer to ChartP

Using procedures described in Example 239, the title compound isobtained as a white solid.

Physical characteristics are as follows:

MS m/z 480, 338, 207, 186, 145, 144, 117, 79, 78, 55

EXAMPLE 241

5-Cyanopyridin-2-yl-sulfonamide, N- 4-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-(Formula P-2, R is 5-cyanopyridin-2-yl)Refer to Chart P

The title compound is prepared using procedures described in Example239.

EXAMPLE 242

2-Pyrazinylsulfonamide, N- 4-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-(Formula P-2, R is 2-pyrazinyl) Refer toChart P

The title compound is prepared using procedures described in Example239.

EXAMPLE 243

2-Pyrimidinylsulfonamide, N- 4-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-(Formula P-2, R is 2-pyrimidinyl) Refer toChart P

The title compound is prepared using procedures described in Example239.

EXAMPLE 244

4-6-Dimethylpyrimidin-2-yl-sulfonamide, N- 4-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-(Formula P-2, R is4,6-dimethylpyrimidin-2-yl) Refer to Chart P

The title compound is prepared using procedures described in Example239.

EXAMPLE 245

4-Methylpyrimidin-2-yl-sulfonamide, N- 4-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)methyl!phenyl!-(Formula P-2, R is 4-methylpyrimidin-2-yl)Refer to Chart P

The title compound is prepared using procedures described in Example239.

PREPARATION 69

6,6-Bis-(2-cyclopropyl-ethyl)-dihydro-pyran-2,4-dione (Formula Q-2)Refer to Chart Q

To a suspension of 150 mg of sodium hydride (60% dispersion in mineraloil) in 4 ml of dry THF under argon atmosphere at 0° C. is addeddropwise 0.38 ml of methyl acetoacetate. After 10 minutes 2.3 ml ofbutyllithium (1.6M in hexanes) is added. After 10 minutes a solution of0.48 g of the compound of formula Q-1 (prepared as described inPreparation 79 (Formula S-4, refer to Chart S)) in 3 ml oftetrahydrofuran is added. The reaction mixture is stirred for 1 hour,then partitioned between ethyl acetate and dilute aqueous hydrogenchloride. The aqueous phase is extracted with two additional portions ofethyl acetate. The organic phases are combined, washed with brine, driedover magnesium sulfate and concentrated under reduced pressure. Theresidue is diluted with 5 mL of methanol and the resulting solutiontreated with 12 mL of water followed by 3.0 ml of 1M aqueous sodiumhydroxide. After 2 hours of vigorous stirring the methanol is removedunder reduced pressure. The aqueous phase is washed once with diethylether; the ether phase is discarded. The aqueous phase is cooled to 0°C., then acidified with dilute aqueous hydrogen chloride. The resultingprecipitate is extracted with four portions of dichloromethane. Thecombined dichloromethane extracts are dried over magnesium sulfate andconcentrated under reduced pressure. The residue is dissolved in diethylether-hexane and the solution is chilled to provide to provide 0.42 g ofthe title compound as a pale yellow solid.

Physical characteristics are as follows:

¹ H NMR δ0.0, 0.4, 0.6, 1.2, 1.7, 2.6, 3.4.

PREPARATION 70

6,6-Bis-(2-cyclopropyl-ethyl)-5,6-dihydro-4-hydroxy-3-1-(3-nitrophenyl)-propyl!-pyran-2-one (Formula Q-3) Refer to Chart Q

To a stirred solution of 0.41 g of the title compound of Preparation 69(Formula Q-2) and 0.25 g of the 3-nitrobenzaldehyde in 5 ml of drytetrahydrofuran is added a solution of 0.44 g of aluminum trichloride in4.5 ml of tetrahydrofuran. After 2 hours, the reaction mixture istreated with 1.0 g of sodium carbonate decahydrate, stirred 10 minutes,diluted with diethyl ether and finally charged with magnesium sulfate.The resulting mixture is filtered through a pad of Celite with diethylether rinses. The filtrates are combined and concentrated under reducedpressure. The resulting residue is charged with 103 mg of copper (I)bromide-dimethyl sulfide complex and 5 ml of dry tetrahydrofuran underan argon atmosphere. The reaction mixture is treated dropwise with 2.5mL of triethyl aluminum (1.0M in hexane) over 1.5 hours. The reaction isthen slowly treated with ice and partitioned between diethyl ether anddilute aqueous hydrogen chloride. The aqueous phase is extracted withthree additional portions of diethyl ether. The combined ether extractsare washed with brine, dried over magnesium sulfate, and concentratedunder reduced pressure. Flash column chromatography of the residue onsilica gel using 20% to 40% ethyl acetate in hexane affords 0.44 g ofthe title compound as a tan foam.

Physical characteristics are as follows:

¹ H NMR δ0.0, 0.4, 0.6, 1.0, 1.2, 1.7-1.9, 2.0-2.4, 2.6, 4.2, 7.5, 7.8,8.1, 8.3

PREPARATION 71

3-1-(3-Amino-phenyl)-propyl!-6,6-bis-(2-cyclopropyl-ethyl)-5,6-dihydro-4-hydroxy-pyran-2-one(Formula Q-4) Refer to Chart Q

To a solution of 0.44 g of the title compound of Preparation 70 (FormulaQ-3) in 6 ml of methanol is added 0.65 g of ammonium formate and 50 mgof 10% palladium on carbon. The black slurry is stirred under argon for3 hours, then filtered through pad of Celite with methanol washes. Thefiltrates are combined and the solvent is removed under reducedpressure. The residue is triturated with four portions ofdichloromethane. The combined dichloromethane washes are concentratedunder reduced pressure to provide 0.37 g of the title compound as awhite foam.

Physical characteristics are as follows:

R_(f) 0.08 (50% diethyl ether in hexane)

EXAMPLE 246

N- 3-(1-6,6-Bis-(2-cyclopropyl-ethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!propyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula Q-5: R₁ is 1-methylimidazol-4-yl) Refer to Chart Q

To a flask containing 57 mg of the title compound of Preparation 71(Formula Q-4) and 24 μl of pyridine in 1.0 ml of dichloromethane isadded 27 mg of 1-methylimidazole-4-sulfonyl chloride. After 6 hours thereaction mixture is concentrated under reduced pressure. The pyridine isazeotroped thrice with toluene. The resulting residue is flash columnchromatographed on silica gel using 2% to 6% methanol in dichloromethaneto provide 51 mg of the title compound as a white foam.

Physical characteristics are as follows:

¹ H NMR δ0.0, 0.4, 0.6, 0.9, 1.1-1.4, 1.7-2.2, 2.5, 3.7, 3.95, 6.9, 7.1,7.4, 7.5

HRMS: 528.2537 (FAB)

EXAMPLE 247

N- 3-(1-6,6-Bis-(2-cyclopropyl-ethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!propyl)phenyl!-5-cyano-2-pyridinesulfonamide(Formula Q-5: R₁ is 5-cyano-2-pyridyl) Refer to Chart Q

Using the general sulfonylation procedure described in Example 246, 57mg of the amine of Preparation 71 (Formula Q-4) is reacted with 30 mg of5-cyanopyridine-2-sulfonyl chloride. Flash column chromatography onsilica gel using 1% to 3% methanol in dichloromethane provides 62 mg ofthe title compound as a tan foam.

Physical characteristics are as follows:

¹ H NMR δ0.0, 0.4, 0.6, 0.9, 1.1-1.4, 1.6-2.2, 2.5, 3.95, 6.9-7.2, 8.0,8.2, 9.0

HRMS: 550.2370 (FAB)

PREPARATION 72

3-Aminopropiophenone (Formula R-2) Refer to Chart R

To a solution of 3-nitropropiophenone (Formula R-1) (1.79 g) in diethylether is added 5% Pt/C catalyst (0.20 g). The resulting suspension isplaced under a hydrogen gas atmosphere and stirred for 6 hours. Thereaction mixture is filtered through a pad of Celite and the pad washedwith additional portions of diethyl ether. The combined filtrates areconcentrated under reduced pressure to provide 1.49 g of the titlecompound as pale yellow, low melting solid.

Physical characteristics are as follows:

¹ H NMR δ1.2, 3.0, 6.9, 7.2-7.4

R_(f) 0.45 (33% ethyl acetate in hexane)

PREPARATION 73

1- 3-(Dibenzyl-amino)-phenyl!-propan-1-one (Formula R-3) Refer to ChartR

To a solution of the title compound of Preparation 72 of Formula R-2(1.5 g) in dichloromethane (50 mL) is added diisopropylethylamine (6.0mL) followed by benzyl bromide (3.6 mL). After stirring for 6 hours thereaction mixture is heated to reflux overnight. The reaction mixture iscooled to room temperature, diluted with diethyl ether (50 mL) andwashed sequentially with dilute aqueous potassium hydrogen sulfate,water, saturated aqueous sodium bicarbonate, and brine. The organiclayer is dried over sodium sulfate and concentrated under reducedpressure. The residue is purified by flash column chromatography onsilica gel eluting with 5% to 20% ethyl acetate in hexane to provide2.38 g of the title compound as pale yellow solid.

Physical characteristics are as follows:

¹ H NMR δ1.1, 2.9, 4.7, 6.9, 7.2-7.4

Anal. Found: C, 83.88; H, 7.03; N, 4.20

MS: 329 (EI)

PREPARATION 74

6- 3-(Dibenzyl-amino)-phenyl!-dihydro-pyran-2,4-dione (Formula R-4)Refer to Chart R

Using the general procedure described in Preparation 69 for theformation of the dihyropyranone ring, the compound of Formula R-3 ofPreparation 73 (1.96 g) is reacted with the dianion of methylacetoacetate and cyclized to provide 0.76 g of the title compound.

Physical characteristics are as follows:

¹ H NMR δ0.8, 1.9, 2.6-2.9, 3.1-3.2, 4.7, 6.5-6.7, 7.1-7.4

MS: 413 (EI)

PREPARATION 75

6- 3-(Dibenzyl-amino)-phenyl!-5,6-dihydro-6-ethyl-4-hydroxy-3-1-(3-nitro-phenyl)-propyl!-pyran-2-one (Formula R-5) Refer to Chart R

Using the general procedure described in Preparation 70, aluminumtrichloride catalyzed condensation of 3-nitrobenzaldehyde with thecompound of Formula R-4 of Preparation 74 (727 mg), followed by coppercatalyzed conjugate addition with triethyl aluminum provides 800 mg ofthe title compound.

Physical characteristics are as follows:

¹ H NMR δ0.6, 1.6-2.1, 2.8, 3.4, 3.8, 4.4, 6.4-6.6, 6.8-7.4, 7.7-8.0

MS: 576 (EI)

PREPARATION 76

6-(3-Amino-phenyl)-3-1-(3-amino-phenyl)-propyl!-6-ethyl-5,6-dihydro-4-hydroxy-pyran-2-one(Formula R-6) Refer to Chart R

Using the general procedure described in Preparation 71, catalytichydrogenation of the compound of Formula R-5 of Preparation 75 (114 mg)with ammonium formate and Pd/C affords 61 mg of the title compound.Alternatively, the compound of Formula R-5 of Preparation 75 (114 mg) isreduced with Pd/C and hydrogen gas to give 72 mg of the title compound.

Physical characteristics are as follows:

¹ H NMR δ0.6-0.9, 1.8-2.1, 3.0, 3.8, 6.4-6.6, 6.95, 7.1

R_(f) 0.40 (10% methanol in dichloromethane)

EXAMPLE 248

N-(3- 1-(6-Ethyl-5,6-dihydro-4-hydroxy-6- 3-((1-methyl-1H-imidazol-4-yl)sulfonyl!amino)phenyl!-2-2H-pyran-3-yl)propyl!phenyl)-1-methyl-1H-imidazole-4-sulfonamide(Formula R-7: R₁ is 1-methylimidazol-4-yl) Refer to Chart R

Using the general sulfonylation procedure described in Example 246, thecompound of Formula R-6 of Preparation 76 (61 mg) is reacted with1-methylimidazole-4-sulfonyl chloride to provide 59 mg of the titlecompound.

Physical characteristics are as follows:

¹ H NMR δ0.3-0.7, 1.6-2.0, 3.0, 3.4-3.7, 6.7-7.5

HRMS: 655.1995 (FAB)

EXAMPLE 249

5-Cyano-N-(3- 1-(6- 3-((5-cyano-2-pyridinyl)sulfonyl!amino)phenyl!-6-ethyl-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl)propyl!phenyl)-2-pyridinesulfonamide(Formula R-7: R is 5-cyano-2-pyridyl) Refer to Chart R

Using the general sulfonylation procedure described in Example 246, thecompound of Formula R-6 of Preparation 76 (66 mg) is reacted with5-cyano-2-pyridine sulfonyl chloride to provide 40 mg of the titlecompound.

Physical characteristics are as follows:

¹ H NMR δ0.3-0.9, 1.3, 1.6-1.9, 3.0, 3.7, 6.6-7.2, 7.9-8.2, 8.8-9.0

HRMS: 699.1679 (FAB)

PREPARATION 77

N-Methoxy-N-methyl-4-pentenoic amide (Formula S-2) Refer to Chart S

To a suspension of 4-pentenoic acid (Formula S-1) (2.00 g) andN,O-dimethylhydroxylamine hydrochloride (2.15 g) in dichloromethane (50mL) at 0° C. is added diisopropylethylamine (11.5 mL) followed bybis(2-oxo-3-oxazolidinyl)phosphinic chloride (5.60 g). After stirringovernight, the reaction mixture is concentrated under reduced pressure.The residue is partioned between dilute aqueous potassium hydrogensulfate and diethyl ether. The aqueous phase is extracted with twoadditional portions of diethyl ether. The organic extracts are combined,washed with brine, dried over sodium sulfate and concentrated underreduced pressure. The residue is purified by flash column chromatographyon silica gel eluting with 50% to 80% diethyl ether in hexane to provide2.58 g of the title compound as a tan oil.

Physical characteristics are as follows:

¹ H NMR δ2.3-2.6, 3.20, 3.70, 4.9-5.1, 5.75-5.95

R_(f) 0.17 (25% diethyl ether in hexane)

PREPARATION 78

Nona-1,8-dien-5-one (Formula S-3) Refer to Chart S

To a flame-dried flask under an argon atmosphere containing a solutionof the title compound of Preparation 77 (Formula S-2) (1.45 g) in drytetrahydrofuran (10 mL) at 0° C. is added 3-butenyl-1-magnesium bromide(20 mL, 1M solution in tetrahydrofuran. (Preparation of this Grignardreagent from magnesium metal and 4-bromo-1-butene is described inJ.Org.Chem. 43:4247 (1978)). After 1 hour at 0° C., the reaction mixtureis warmed to room temperature; after 1 hour at room temperature, thereaction mixture is poured into dilute aqueous potassium hydrogensulfate and partioned against diethyl ether. The aqueous phase isextracted with three additional portions of diethyl ether. The organicextracts are combined, washed with brine, dried over sodium sulfate andcarefully concentrated under reduced pressure. The resulting liquid ispurified by distillation to provide 1.32 g of the title compound as atan oil.

Physical characteristics are as follows:

¹ H NMR δ2.3, 2.5, 5.0, 5.7-5.9

R_(f) 0.66 (25% diethyl ether in hexane)

PREPARATION 79

1,5-Dicyclopropyl-pentan-3-one (Formula S-4) Refer to Chart S

To a flame-dried flask under an argon atmosphere equipped with a refluxcondenser containing zinc metal (8.0 g) and cuprous chloride (1.25 g) isadded a solution of the title compound of Preparation 78 (Formula S-3)(1.32 g) in dry diethyl ether (10 mL). The resulting suspension ischarged with diiodomethane (5.0 mL) and the reaction flask placed in 40°C. ultrasound bath (Branson 2200) and sonicated. After 2 hours heatingis ceased and sonication is continued overnight. The reaction mixture isthen diluted with diethyl ether (50 mL), cooled to 0° C., and treatedwith excess saturated aqueous ammonium chloride. After 0.25 hours ofvigorous stirring, the mixture is filtered and the layers separated. Theaqueous phase is extracted with two additional portions of diethylether. The organic extracts are combined and washed sequentially withdilute aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate,brine; dried over magnesium sulfate and then carefully concentratedunder reduced pressure. The resulting residue is purified by flashcolumn chromatography on silica gel eluting with 5% to 20% diethyl etherin hexane to provide 0.48 g of the title compound as an oil.

Physical characteristics are as follows:

¹ H NMR δ0.0, 0.4, 0.65, 1.45, 2.50

R_(f) 0.44 (10% diethyl ether in hexane)

PREPARATION 80

3-2,2-Dimethyl-1-(3-nitro-phenyl)-propyl!-5,6-dihydro-4-hydroxy-6-phenethyl-6-propyl-pyran-2-one(Formula T-3) Refer to Chart T

To a flame-dried flask containing a slurry of 977 mg of activated zincmetal in 1.0 mL of dry tetrahydrofuran under an argon atmosphere isadded 40 μL of 1,2-dibromoethane. The mixture is placed in 45° C.ultrasound bath (Branson 2200) and sonicated with stirring. After 10minutes the mixture is treated with 0.25 mL of chlorotrimethylsilane(1.0M in tetrahydrofuran). After 10 minutes, the mixture is diluted with4 mL of tetrahydrofuran and treated dropwise with 1.50 mL of2-iodo-2-methylpropane. The mixture is stirred and sonicated at 45° C.for an additional 3 hours, then cooled to room temperature withoutstirring. In a separate flask 954 mg of anhydrous lithium chloride isheated in an 110° C. oil bath in vacuo for 1 hour. The LiCl flask iscooled to room temperature, placed under an argon atmosphere and chargedwith 1.01 g of copper (I) cyanide followed by 10 mL of tetrahydrofuran.After 15 minutes of stirring at room temperature, the LiCl--CuCN mixtureis cooled to -30° C. and treated via cannula with the organozinc mixtureprepared as described above in the first flask. The reaction flask iswarmed from -30° C. to 0° C., stirred 10 minutes then cooled to -78° C.The preparation of this organometallic reagent is analogous toliterature procedures (Org. Syn. 70:195-203 (1991)) described forrelated reagents.

In a separate flask a stirred solution of 1.56 g of6-phenethyl-6-propyldihydro-pyran-2,4-dione of Formula T-2 (preparedfrom the compound of Formula T-1 as described in Preparation 17 above)and 915 mg of the 3-nitrobenzaldehyde in 22 mL of dry tetrahydrofuran istreated with a solution of 1.60 g of aluminum trichloride in 14 mL oftetrahydrofuran. After 2 hours, the reaction mixture is treated with 3.6g of sodium carbonate decahydrate, stirred 5 minutes, diluted withdiethyl ether and finally charged with magnesium sulfate. The resultingmixture is filtered through a pad of Celite with diethyl ether washes.The filtrates are combined and concentrated under reduced pressure. Theresulting residue is charged with 9 mL of dry tetrahydrofuran under anargon atmosphere and is added via cannula to the cooled (-78° C.)organometallic reagent solution prepared as described above. After 0.5hours the reaction mixture is warmed to 0° C. After 0.5 hours at 0° C.the reaction is poured into cold dilute ammonium chloride and theaqueous phase is made acidic with dilute aqueous hydrogen chloride. Themixture is treated with ethyl acetate and filtered through a pad ofCelite with ethyl acetate washes. The layers are separated and theaqueous phase is extracted with three additional portions of ethylacetate. The combined ethyl acetate extracts are washed with aqueoussodium thiosulfate, brine; dried over magnesium sulfate, andconcentrated under reduced pressure. Flash column chromatography of theresidue on silica gel eluting with 30% to 50% ethyl acetate in hexaneaffords 1.73 g of the title compound as a tan foam.

Physical characteristics are as follows:

¹ H NMR δ0.9, 1.1, 1.3, 1.6-2.0, 2.5-2.8, 4.3, 6.9-7.3, 7.8, 8.0, 8.5

HRMS: 452.2449 (FAB)

PREPARATION 81

3-1-(3-Amino-phenyl)-2,2-dimethyl-propyl!-5,6-dihydro-4-hydroxy-6-phenethyl-6-propyl-pyran-2-one(Formula T-4) Refer to Chart T

To a solution of 1.72 g of the title compound of Preparation 80 (FormulaT-3) in 25 mL of methanol is added 3.0 g of ammonium formate and 400 mgof 10% palladium on carbon. The black slurry is stirred under nitrogenfor 3 hours, then filtered through pad of Celite with methanol washes.The filtrates are combined and the solvent is removed under reducedpressure. The residue is repeatedly triturated with portions ofdichloromethane and the combined dichloromethane washes concentratedunder reduced pressure. The residue is flash column chromatographed onsilica gel eluting with 10% ethyl acetate in dichloromethane to provide1.48 g of the title compound as a white foam.

Physical characteristics are as follows:

¹ H NMR δ0.7-0.9, 1.1, 1.3-2.6, 4.2, 6.55, 6.9-7.3

HRMS: 422.2686 (FAB)

EXAMPLE 250

N- 3-(1-5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula T-5: R₁ is 1-methylimidazol-4-yl) Refer to Chart T

To a solution of 1.48 g of the title compound of Preparation 81 (FormulaT-4) in 25 ml of dichloromethane at 0° C. is added 0.57 mL of pyridinefollowed by 632 mg of 1-methylimidazole-4-sulfonyl chloride. After 3hours the reaction mixture is warmed to room temperature andconcentrated under reduced pressure. Pyridine is azeotroped thrice withtoluene. The resulting residue is flash column chromatographed on silicagel using 2% to 6% methanol in dichloromethane to provide 1.7 g of thetitle compound as a white solid.

Physical characteristics are as follows:

¹ H NMR δ0.8-1.0, 0.97, 1.35, 1.6-2.0, 2.5-2.7, 3.6, 4.1, 6.9-7.5

HRMS: 566.2684

The individual stereoisomers of this compound are the following:

N- 3-(1(S)-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula KK-8 wherein R₄ is 1-methyl-1H-imidazol-4-yl) Refer to ChartKK;

N- 3-(1(R)-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula LL-8 wherein R₄ is 1-methyl-1H-imidazol-4-yl) Refer to ChartLL;

N- 3-(1(S)-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula MM-8 wherein R₄ is 1-methyl-1H-imidazol-4-yl) Refer to ChartMM; and

N- 3-(1(R)-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula NN-8 wherein R₄ is 1-methyl-1H-imidazol-4-yl) Refer to ChartNN.

EXAMPLE 251

5-Cyano-N- 3-(1-5,6-dihydro-4-hydoxy-2-oxo-6-(2-phenethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide(Formula T-5: R₁ is 5-cyano-2-pyridyl) Refer to Chart T

Using the general sulfonylation procedure described in Example 250, 42mg of the amine of Preparation 81 (Formula T-4) is reacted with 20 mg of5-cyanopyridine-2-sulfonyl chloride. Flash column chromatography onsilica gel using 1% to 3% methanol in dichloromethane provides 56 mg ofthe title compound as a white foam.

Physical characteristics are as follows:

¹ H NMR δ0.8-1.0, 0.92, 1.35, 1.6-2.0, 2.5-2.7, 4.0, 6.9-7.4, 8.0, 8.9

HRMS: 588.2532

PREPARATION 82

N-Methoxy, N-methyl 3-(4-fluorophenyl)propionamide (Formula U-2) Referto Chart U

To a cold (0°), stirred solution of 5.0 g of 3-(4-fluorophenyl)propionicacid of Formula U-1, 3.2 g of (N,O)-dimethylhydroxylamine hydrochloride,and 11.4 ml of diisopropylethylamine in 40 ml of dichloromethane isslowly added a solution of 5.0 ml of diethyl cyanophosphonate in 10 mlof dichloromethane. After 18 hours, the solution is concentrated underreduced pressure. The residue is dissolved in ethyl acetate, and thesolution washed with dilute HCl, water, aqueous sodium bicarbonate, andbrine, and dried over magnesium sulfate. Removal of the solvent underreduced pressure provides 6.94 g of the title compound.

Physical characteristics are as follows:

¹ H NMR δ2.7, 2.9, 3.17, 3.61, 7.0, 7.2 ppm

IR 1665, 1511, 1222, 1033, 990 cm⁻¹

TLC R_(f) 0.34 (5% ethyl acetate in dichloromethane)

PREPARATION 83

1-(4-Fluorophenyl)-3-hexanone (Formula U-3) Refer to Chart U

A stirred solution of 4.68 g of the title compound of Preparation 82(Formula U-2) in 25 ml of dry THF under argon is cooled to -15°, and tothe solution is added 17 ml of a 1M solution of propylmagnesium chloridein ether. The resulting solid mass is warmed to 0°, kept at thattemperature for 90 minutes, then partitioned between ether and colddilute HCl. The aqueous phase is extracted with one additional portionof ether, and the combined organic phase washed with brine and driedover magnesium sulfate. Following removal of solvent by distillation atatmospheric pressure, the residue is purified by evaporativedistillation (ca 160° @ 13 mmHg) to provide 3.51 g of the title compoundas a colorless liquid.

Physical characteristics are as follows:

¹ H NMR δ0.89, 1.6, 2.36, 2.7, 2.9, 6.9, 7.1 ppm

IR 2965, 1714, 1511, 1222 cm⁻¹

PREPARATION 84

5,6-Dihydro-4-hydroxy-6-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-2-one(Formula U-4) Refer to Chart U

To a cold (0°), stirred slurry of 950 mg of sodium hydride (60%dispersion in mineral oil) in 30 ml of dry THF, under argon, is addeddropwise 2.3 ml of methyl acetoacetate. After 5 minutes, 13.5 ml ofbutyllithium (1.6M in hexanes) is added, and the mixture stirred another5 minutes before addition of a solution of 3.51 g of the title compoundof Preparation 83 (Formula U-3) in 4 ml of THF. The solution is stirredfor 1 hour, then partitioned between ethyl acetate and cold dilute HCl.The aqueous phase is extracted with two additional portions of ethylacetate, and the combined organic phase washed with brine and dried overmagnesium sulfate. Removal of the solvent under reduced pressureprovides the intermediate ester with the following physicalcharacteristics: TLC R_(f) 0.45 (50% ethyl acetate in hexane).

The ester is stirred in 20 ml of 1M sodium hydroxide, 80 ml of water,and 40 ml of methanol for 90 minutes, then the methanol is removed underreduced pressure. The aqueous phase is washed once with ether, the etherphase being discarded, and then acidified with dilute HCl. The resultingprecipitate is extracted with four portions of dichloromethane, and theextract dried over magnesium sulfate and concentrated under reducedpressure. The residue is dissolved in 1:1 ether-hexane and the solutionchilled to provide crystals, which are filtered, washed withether-hexane, and dried under vacuum to afford 3.24 g of the titlecompound.

Physical characteristics are as follows:

¹ H NMR δ0.96, 1.4, 1.8, 2.0, 2.5, 2.7, 7.0, 7.1 ppm

IR 2962, 1655, 1604, 1510, 1221 cm⁻¹

M.P. 113°-114.5°

Anal. Found: C, 68.85; H, 6.99

MS: M+ 278

R_(f) 0.44 (5% methanol in dichloromethane)

PREPARATION 85

3-(1-(3-Benzyloxycarbonylaminophenyl)-2,2-dimethylpropyl)-5,6-dihydro-4-hydroxy-6-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-2-one(Formula U-6: R₁ is tert-butyl) Refer to Chart U

To a stirred solution of 3.06 g of the title compound of Preparation 84(Formula U-4) and 2.81 of the title compound of Preparation 6 above(Formula B-2) in 30 ml of dry THF is added a solution of 2.93 g of AlCl₃in 20 ml of THF. After two hours, 6.4 g of sodium carbonate decahydrateis added, and after five minutes the mixture is filtered through Celitewith ether rinses. Removal of the solvent under reduced pressureprovides the intermediate benzylidene compound of Formula U-5.

To this is added, under argon, 1.13 g of copper (I) bromide-dimethylsulfide complex and 30 ml of THF, and the mixture is cooled to 0° fordropwise addition of 18.1 ml of tert-butylmagnesium chloride (1.0M inTHF). After 10 minutes, the reaction is partitioned between ether andcold dilute HCl. The organic phase is washed with brine, dried overmagnesium sulfate, and concentrated under reduced pressure. Flashchromatography of the residue on silica gel using 30-35% ethyl acetatein hexane affords 1.83 g of the title compound as a foam.

Physical characteristics are as follows:

¹ H NMR δ0.87, 1.1, 1.3, 1.6-2.2, 2.5, 5.12, 6.8-7.6 ppm

HRMS: 574.2955

R_(f) 0.29 (35% ethyl acetate in hexane)

PREPARATION 86

3-(1-(3-Aminophenyl)-2,2-dimethylpropyl)-5,6-dihydro-4-hydroxy-6-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-2-one(Formula U-7: R₁ is tert-butyl) Refer to Chart U

A mixture of 1.83 g of the title compound of Preparation 85 (FormulaU-6), 2.0 g of ammonium formate, and 400 mg of 10% palladium on carbonin 25 ml of methanol is stirred under argon for 90 minutes, thenfiltered through Celite. The solvent is removed under reduced pressureand the residue flash chromatographed on silica gel using 10% ethylacetate in dichloromethane to provide 1.24 g of the title compound as awhite foam.

Physical characteristics are as follows:

R_(f) 0.28 (10% ethyl acetate in dichloromethane)

The compound of Formula U-7 wherein R₁ is ethyl is prepared from U-4 byanalogous procedures as in the preparation of U-7 wherein R₁ istert-butyl (Preparations 85 and 86).

EXAMPLE 252

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula U-8: R₁ is tert-butyl, R₂ is 1-methylimidazole-4-yl) Refer toChart U

To a cold (0°), stirred solution of 88 mg of the title compound ofPreparation 86 (Formula U-7) and 32 μl of pyridine in 0.5 ml ofdichloromethane is added 36 mg of 1-methylimidazole-4-sulfonyl chloride.After 90 minutes the reaction mixture is flash chromatographed on silicausing 3-4% methanol in dichloromethane to provide 112 mg of the titlecompound as a white foam.

Physical characteristics are as follows:

¹ H NMR δ0.8-1.0, 0.96, 1.3, 1.7, 2.35, 2.5, 3.6, 3.7, 6.8-7.5 ppm

HRMS: 583.2525

R_(f) 0.31 (5% methanol in dichloromethane)

EXAMPLE 253

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula U-8: R₁ is tert-butyl, R₂ is 5-cyanopyridine-2-yl) Refer toChart U

Using the general sulfonylation procedure of Example 252, 88 mg of theamine of Preparation 86 (Formula U-7, R₁ is tert-butyl) is reacted with5-cyanopyridine-2-sulfonyl chloride. Flash chromatography on silicausing 10-15% ethyl acetate in dichloromethane provides 107 mg of thetitle compound as an amorphous white solid.

Physical characteristics are as follows:

¹ H NMR δ0.92, 1.3, 1.7, 2.5, 6.8-7.5, 8.0, 8.9 ppm

HRMS: 606.2423

EXAMPLE 254

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6-(2-(4-fluorophenyl)ethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula U-8: R₁ is ethyl, R₂ is 1-methylimidazole-4-yl) Refer to ChartU

Using the general sulfonylation procedure of Example 252, 82 mg of theamine of Formula U-7, wherein R₁ is ethyl, is reacted with1-methylimidazole-4-sulfonyl chloride. Flash chromatography on silicausing 3% methanol in dichloromethane provides 101 mg of the titlecompound as an amorphous white solid.

Physical characteristics are as follows:

¹ H NMR δ0.8, 1.3, 1.6-2.2, 2.5, 3.5, 3.6, 3.9, 6.8-7.4 ppm

HRMS: 555.2192

R_(f) 0.29 (5% methanol in dichloromethane)

EXAMPLE 255

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula U-8: R₁ is ethyl, R₂ is 5-cyanopyridine-2-yl) Refer to Chart U

Using the general sulfonylation procedure of Example 252, 82 mg of theamine of Formula U-7, wherein R₁ is ethyl, is reacted with5-cyanopyridine-2-sulfonyl chloride. Flash chromatography on silicausing 10-15% ethyl acetate in dichloromethane provides 101 mg of thetitle compound as an amorphous white solid.

Physical characteristics are as follows:

¹ H NMR δ0.9, 1.3, 1.6-2.2, 2.5, 3.9, 6.9-7.3, 8.0, 8.1, 8.9 ppm

HRMS: 557.2059

R_(f) 0.44 (20% ethyl acetate in dichloromethane)

PREPARATION 87

1,5-Bis-(4-fluorophenyl)-penta-1,4-dien-3-one (Formula V-2) Refer toChart V

To a rapidly stirred, ambient temperature solution of 10 g of sodiumhydroxide in 100 ml of water and 80 ml of ethanol is added a mixture of12.4 g of 4-fluorobenzaldehyde of Formula V-1 and 2.9 g of acetone.After 45 minutes, the resulting precipitate is filtered off, washed wellwith water, and dried under vacuum. Recrystallization from ethylacetate-hexane yields 10.7 g of the title compound as light yellowplatelets.

Physical characteristics are as follows:

¹ H NMR δ6.9-7.2, 7.6-7.7 ppm

IR 1653, 1587, 1508, 984, 835 cm⁻¹

MS: M+ 270

Anal. Found: C, 75.40; H, 4.41

R_(f) 0.35 (dichloromethane)

M.P. 152°-154°

PREPARATION 88

1,5-Bis-(4-fluorophenyl)-pentane-3-one (Formula V-3) Refer to Chart V

To a solution of 5.41 g of dienone of Preparation 87 (Formula V-2) in 10ml of THF and 50 ml of methanol is added 2.0 g of magnesium chips. Awater bath is used to maintain the temperature of the reaction nearambient. After the magnesium has been consumed, the reaction mixture ispartitioned between dichloromethane and dilute HCl, with two additionaldichloromethane extractions of the aqueous phase. The combined organicphase is dried over magnesium sulfate and concentrated under reducedpressure. Flash chromatography of the residue on silica using 50%dichloromethane in hexane affords 3.66 g of the title compound as ayellow oil.

Physical characteristics are as follows:

¹ H NMR δ2.67, 2.85, 6.9, 7.1 ppm

IR 2932, 1716, 1603, 1511, 1223, 1159, 828 cm⁻¹

MS: M+ 274

R_(f) 0.28 (50% dichloromethane in hexane)

PREPARATION 89

4-Hydroxy-5,6-dihydro-6,6-bis(2-(4-fluorophenyl)ethyl)-2H-pyran-2-one(Formula V-4) Refer to Chart V

Using the general acetoacetate condensation and ring closure procedureof Preparation 84 (Formula U-4), 3.9 g of the ketone of Preparation 88(Formula V-3) is converted to 2.86 g of the title compound, which may berecrystallized from dichloromethane-hexane.

Physical characteristics are as follows:

¹ H NMR δ2.1, 2.57, 2.7, 7.0, 7.1 ppm

IR 2924, 1659, 1578, 1508, 1241, 1216 cm⁻¹

MS: M+ 358

Anal. Found: C, 70.17; H, 5.50

M.P. 140°-141°

PREPARATION 90

3- 1-(3-Benzyloxycarbonylaminophenyl)-2,2-dimethylpropyl!-6,6-bis2-(4-fluorophenyl)ethyl!-4-hydroxy-5,6-dihydro-2H-pyran-2-one (FormulaV-6: R₁ is tert-butyl) Refer to Chart V

Using the general benzylidene condensation and cuprate additionprocedure of Preparation 85 (Formula U-6), 1.075 g of the dihydropyroneof Preparation 89 (Formula V-4) is converted to 707 mg of the titlecompound (via the intermediate compound of Formula V-5), which ispurified by flash chromatography on silica gel using 40% ethyl acetatein hexane.

Physical characteristics are as follows:

¹ H NMR δ1.07, 2.0, 2.6, 3.9, 5.16, 6.8-7.5 ppm

HRMS: 654.3023

R_(f) 0.25 (40% ethyl acetate in hexane)

PREPARATION 91

3- 1-(3-Aminophenyl)-2,2-dimethylpropyl!-6,6-bis2-(4-fluorophenyl)ethyl!-4-hydroxy-5,6-dihydro-2H-pyran-2-one (FormulaV-7: R₁ is tert-butyl) Refer to Chart V

Using the general transfer hydrogenolysis procedure of Preparation 86(Formula U-7), 684 mg of the carbamate of Preparation 90 (Formula V-6,R₁ is tert-butyl) is converted to 497 mg of the title compound, which ispurified by flash chromatography on silica gel using 5-10% ethyl acetatein dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ1.09, 2.0, 2.6, 6.8-7.1 ppm

R_(f) 0.34 (10% ethyl acetate in dichloromethane)

The compound of Formula V-7 wherein R₁ is ethyl is prepared from V-4 byanalogous procedures as in the preparation of V-7 wherein R₁ istert-butyl

(Preparations 90 and 91).

EXAMPLE 256

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-(4-fluorophenyl)ethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula V-8: R₁ is tert-butyl, R₂ is 1-methylimidazole-4-yl) Refer toChart V

Using the general sulfonylation procedure of Example 252, 78 mg of theamine of Preparation 91 (Formula V-7, R₁ is tert-butyl) is reacted with1-methylimidazole-4-sulfonyl chloride. Flash chromatography on silicausing 3-4% methanol in dichloromethane provides 92 mg of the titlecompound as an amorphous white solid.

Physical characteristics are as follows:

¹ H NMR δ0.94, 1.7-2.1, 2.5, 3.50, 6.8-7.4 ppm

HRMS: 664.2647

R_(f) 0.34 (5% methanol in dichloromethane)

EXAMPLE 257

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-(4-fluorophenyl)ethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula V-8: R₁ is tert-butyl, R₂ is 5-cyanopyridine-2-yl) Refer toChart V

Using the general sulfonylation procedure of Example 252, 78 mg of theamine of Preparation 91 (Formula V-7, R₁ is tert-butyl) is reacted with5-cyanopyridine-2-sulfonyl chloride. Flash chromatography on silicausing 10-15% ethyl acetate in dichloromethane provides 91.5 mg of thetitle compound as an amorphous white solid.

Physical characteristics are as follows:

¹ H NMR δ0.92, 1.9, 2.6, 3.2, 6.8-7.5, 8.0, 8.9 ppm

HRMS: 686.2488

R_(f) 0.28 (10% ethyl acetate in dichloromethane)

EXAMPLE 258

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-(4-fluorophenyl)ethyl)-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula V-8: R₁ is ethyl, R₂ is 1-methylimidazole-4-yl) Refer to ChartV

Using the general sulfonylation procedure of Example 252, 74 mg of theamine of Formula V-7, wherein R₁ is ethyl, is reacted with1-methylimidazole-4-sulfonyl chloride. Flash chromatography on silicausing 3-4% methanol in dichloromethane provides 77 mg of the titlecompound as an amorphous white solid.

Physical characteristics are as follows:

¹ H NMR δ0.87, 2.0, 2.6, 3.62, 4.0, 4.05, 6.9-7.5 ppm

HRMS: 636.2350

R_(f) 0.31 (5% methanol in dichloromethane)

EXAMPLE 259

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-(4-fluorophenyl)ethyl)-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula V-8: R₁ is ethyl, R₂ is 5-cyanopyridine-2-yl) Refer to Chart V

Using the general sulfonylation procedure of Example 252, 74 mg of theamine of Formula V-7, wherein R₁ is ethyl, is reacted with5-cyanopyridine-2-sulfonyl chloride. Flash chromatography on silicausing 10% ethyl acetate in dichloromethane provides 83 mg of the titlecompound as an amorphous white solid.

Physical characteristics are as follows:

¹ H NMR δ0.83, 2.0, 2.6, 3.96, 6.8-7.2, 8.0, 8.8 ppm

HRMS: 658.2200

R_(f) 0.49 (10% ethyl acetate in dichloromethane)

EXAMPLE 260

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is tert-butyl, R₄ is5-cyanopyridine-2-yl) Refer to Chart D

Using the general sulfonylation procedure of Example 252, 54 mg of theamine of Formula D-5 (R₁ and R₂ are propyl, R₃ is tert-butyl), preparedby procedures analogous to those described for the preparation of D-5(where R₁ is phenethyl, R₂ is propyl, R₃ is ethyl) in Preparation 20, iscoupled with 5-cyanopyridine-2-sulfonyl chloride of Formula D-7 (R₄ is5-cyanopyridine-2-yl) to yield, after flash chromatography on silica gelusing 10-15% ethyl acetate in dichloromethane, 62 mg of the titlecompound as an amorphous solid.

Physical characteristics are as follows:

¹ H NMR δ0.90, 1.2-1.8, 2.5, 7.0-7.4, 8.1, 8.2, 8.9 ppm

HRMS: 525.2305

R_(f) 0.44 (20% ethyl acetate in dichloromethane)

EXAMPLE 261

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is tert-butyl, R₄ is1-methylimidazole-4-yl) Refer to Chart D

Using the general sulfonylation procedure of Example 252, 54 mg of theamine of Formula D-5 (R₁ and R₂ are propyl, R₃ is tert-butyl), iscoupled with 1-methylimidazole-4-sulfonyl chloride of Formula D-7 (R₄ is1-methylimidazole-4-yl) to yield, after flash chromatography on silicagel using 3-5% methanol in dichloromethane, 53 mg of the title compoundas an amorphous solid.

Physical characteristics are as follows:

¹ H NMR δ0.9, 0.96, 1.2-1.8, 2.5, 3.6, 3.7, 6.9-7.5 ppm

MS: 503.2422

R_(f) 0.26 (5% methanol in dichloromethane)

EXAMPLE 262

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is ethyl, R₄ is5-cyanopyridine-2-yl) Refer to Chart D

Using the general sulfonylation procedure of Example 252, 67 mg of theamine of Formula D-5 (R₁ and R₂ are propyl, R₃ is ethyl) of Preparation20 is coupled with 5-cyanopyridine-2-sulfonyl chloride of Formula D-7(R₄ is 5-cyanopyridine-2-yl) to yield, after flash chromatography onsilica gel using 10% ethyl acetate in dichloromethane, 78 mg of thetitle compound as an amorphous solid.

Physical characteristics are as follows:

¹ H NMR δ0.6-1.0, 1.2-1.8, 3.4, 3.5, 6.9-7.4, 8.0-8.2, 8.9 ppm

HRMS: 498.2072

R_(f) 0.38 (15% ethyl acetate in dichloromethane)

EXAMPLE 263

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is5-cyanopyridine-2-yl) Refer to Chart D

Using the general sulfonylation procedure of Example 252, 79 mg of theamine of Formula D-5 (R₁ is phenethyl, R₂ is propyl, R₃ is ethyl) ofPreparation 20 is coupled with 5-cyanopyridine-2-sulfonyl chloride ofFormula D-7 (R₄ is 5-cyanopyridine-2-yl) to yield, after flashchromatography on silica gel using 10% ethyl acetate in dichloromethane,102 mg of the title compound as an amorphous solid.

Physical characteristics are as follows:

¹ H NMR δ0.7-1.0, 1.2-2.6, 3.4, 3.5, 6.9-7.3, 7.9-8.2, 8.9 ppm

HRMS: 560.2231

R_(f) 0.37 (15% ethyl acetate in dichloromethane)

EXAMPLES 264-265

The following compounds are prepared using the general sulfonylationprocedure of Example 246. The requisite amine is prepared analogouslyfrom the compound of Formula Q-1 (Preparation 69) following Preparations80 and 81.

264) N- 3-(1-6,6-Bis-(2-cyclopropyl-ethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethyl-propyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide

Physical characteristics are as follows:

¹ H NMR δ0.0, 0.4, 0.6, 1.0, 1.2, 1.7, 2.5, 3.7, 4.1, 6.9-7.6

HRMS: 556.2833 (FAB)

265) N- 3-(1-6,6-Bis-(2-cyclopropyl-ethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethyl-propyl)phenyl!-5-cyano-2-pyridinesulfonamide

Physical characteristics are as follows:

¹ H NMR δ0.0, 0.4, 0.6, 1.0, 1.2, 1.7, 2.5, 4.1, 7.0-7.5, 8.0, 8.1, 9.0

HRMS: 578.2689 (FAB)

PREPARATION 92

(3(2E),4S)-3-(2-pentenyl)-4-phenyl-2-oxazolidinone (Formula W-4) Referto Chart W

A 1 L round-bottomed flask with nitrogen inlet and addition funnel ischarged with 6.92 g of (S)-(+)-4-phenyl-2-oxazolidinone and 250 mL oftetrahydrofuran and then cooled to -78° C. To the aforementionedsolution is added 25.6 mL of n-butyl lithium during which time a whitesolid separated from the reaction solution, W-3. To that suspension isadded 4.88 g of trans-2-pentenoyl chloride of formula W-2 (prepared fromthe treatment of commercially available trans-2-pentenoyl acid offormula W-1 with oxalyl chloride) in a small volume of THF. Theresulting pale yellow homogeneous solution is allowed to warm to roomtemperature and stirred for another 20 min. The reaction mixture isquenched by the addition of saturated ammonium chloride solution and isextracted with ethyl acetate. The organic layer is separated, washedwith brine and water, dried over magnesium sulfate, filtered andconcentrated to give a white solid. Recrystallization from hot hexanegives 9.13 g of the title compound.

Physical characteristics are as follows:

MP 86°-88° C.

¹ H NMR (CDCl₃) δ7.42-7.23, 7.18-7.09, 5.49, 4.70, 4.28, 2.28, 1.08 ppm.

α!_(D) (CHCl₃)=+109

Anal. found: C, 68.59; H, 6.25; N, 5.70

PREPARATION 93

(3(3R),4S)-3- 3-(3-Aminophenyl)-1-oxopentyl!-4-phenyl-2-oxazolidinone(Formula W-5) Refer to Chart W

A 1 L three-necked, round-bottomed flask with nitrogen inlet andaddition funnel is charged with 8.90 g of copper(I) bromide-dimethylsulfide complex and 125 mL of THF and then cooled to -40° C. To thatsuspension is added 43 mL of a 1M solution (in THF) of 3-bis(trimethylsilyl)amino!phenylmagnesium chloride dropwise over 15minutes. The reaction mixture is warmed 0° C. for 30 minutes and then a25 mL THF solution containing 8.85 g of(3(2E),4S)-3-(2-pentenoyl)-4-phenyl-2-oxazolidinone of Preparation 92(formula W-4) is added. The reaction mixture is stirred for 30 minutesat 0° C. and quenched by the addition of 1N HCl and then the pHreadjusted with 1N NaOH to pH 8. The reaction is washed with water,brine and the organic is dried (Na₂ SO₄). The organic solvent isevaporated in vacuo and the resulting oil chromatographed over 600 g ofsilica gel, eluting with ethyl acetate/hexane to afford 7.91 g of thetitle product.

Physical characteristics are as follows:

MP 94°-95° C.

¹ H NMR (CDCl₃) δ7.28-7.25, 7.07-6.99, 6.60-6.51, 5.38, 4.63, 4.16,3.52-3.44, 3.10-2.92, 1.65-1.53, 0.76 ppm.

IR (mineral oil) 3437, 3355, 1773, 1696, 1605, 1337, 1322, 1299, 1263,1212, 1096, 1070, 791, 762, 704 cm⁻¹.

Anal. found: C, 71.00; H, 6.67; N, 8.17

EI-MS: M+!=338.

α!_(D) (19.87 mg/2 mL CHCl₃)=+60°

PREPARATION 94

3- 3-(3-Bis(phenylmethyl)amino!phenyl)-1-oxopentyl!-4-phenyl-2-oxazolidinone,(3R)(4S) (Formula W-6) Refer to Chart W

To a mixture of 25 mL of Na₂ CO₃ and 80 mL of methylene chloride wasadded 7.90 g of (3(3R),4S)-3-3-(3-aminophenyl)-1-oxopentyl!-4-phenyl-2-oxazolidinone of Preparation93 (formula W-5) followed by 15.94 g of benzyl bromide. That mixture isheated at 65° C. for 18 hours, the methylene chloride layer separated,dried (Na₂ SO₄) and solvent evaporated to yield the crude product as adark viscous oil. That oil is chromatographed over 700 g of silica geleluding with 25% ethyl acetate/hexane to yield 8.55 g of the titlecompound.

Physical characteristics are as follows:

MP 92°-3° C.

¹ H NMR (CDCl₃) δ7.24, 7.02, 6.53, 5.34, 4.59, 4.14, 3.44, 3.07, 2.89,1.50, 0.64 ppm

Anal. found: C, 78.47; H, 6.68; N, 5.26

α!_(D) (19.602 mg/2 mL CHCl₃)=+32°

PREPARATION 95

(3R)(4S) 3- 3-(3-bis(phenylmethyl)amino!phenyl)-2-(2-methyl-1,3-dioxolan-2-yl)-1-oxopentyl!-4-phenyl-2-oxazolidinone(Formula W-8) Refer to Chart W

To 25 mL of methylene chloride is added 2.1 g of the amide of formulaW-6 of Preparation 94 and the resulting solution cooled to -78° C. underan atmosphere of nitrogen. To that solution is added 872 μL of neatTiCl₄ followed by the addition of 732 μL of diisopropylethylamine. Theresulting mixture is warmed to 0° C. for 30 minutes and then cooled backto -78° C. and 1.3 g of 2-methoxy-2-methyl-1,3-dioxolane of formula W-7and the resulting reaction is warmed to 0° C. and stirred for 1 hour,then quenched with saturated ammonium chloride and extracted withmethylene chloride. The organic extract is dried (Na₂ SO₄) and solventremoved in vacuo to afford the crude material. Silica gel chromatographyusing 100 g of support and eluding with 10% hexane/methylene chlorideafforded 1.76 g of the title product.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.36, 7.08, 5.99, 5.42, 4.80, 4.68, 4.60, 4.25, 3.68,3.57, 3.48, 3.07, 2.90, 1.5, 0.86, 0.54 ppm

Anal. found: C, 75.34; H, 6.99; N, 4.87

α!_(D) (18.086 mg/2 mL CHCl₃)=+25°

PREPARATION 96

(3R)(4S)-3- 2-acetyl-3-3-(bis(phenylmethyl)amino)phenyl!-1-oxopentyl!-4-phenyl-2-oxazolidinone(Formula W-9) Refer to Chart W

To 25 mL of tetrahydrofuran and 10 mL of 30% HClO₄ is added 5.0 g of thetitle compound of Preparation 95 (formula W-8) and the resultingsolution stirred at 40° C. for 3 hours. The reaction is neutralized withsaturated NaHCO₃ to pH 8 and then extracted with 400 mL of ether. Theether layer is washed with water, brine and then dried (Na₂ SO₄) andsolvent evaporated in vacuo to afford an oil. Chromatography over 300 gof silica gel eluting with 15% acetone/hexane afforded 4.12 g of thetitle compound.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.31, 7.08, 6.59, 6.55, 5.42, 4.67, 4.61, 4.22, 3.09,1.63, 1.56, 0.61 ppm

Anal. found: C, 77.11; H, 6.76; N, 4.98

α!_(D) (20.172 mg/2 mL CHCl₃)=-10°

PREPARATION 97

(3R)(4S) 3- 2- 1-(3-bis(phenylmethyl)amino!phenyl)propyl!-5-hydroxy-1,3-dioxo-5-propyloctyl!-4-phenyl-2-oxazolidinone(Formula W-10) Refer to Chart W

To 25 mL of methylene chloride is added 1.32 g of the compound ofPreparation 96 (formula W-9) and the resulting solution cooled to -78°C. under an atmosphere of nitrogen. To that solution is added 279 μL ofTiCl₄ and 450 μL of diisopropylethylamine and stirring continued for 1hour. To this solution is added 689 μL of heptanone and the reactiontemperature raised to 0° C. for 1.5 hours. The reaction is then quenchedby the addition of a saturated ammonium chloride solution and themixture extracted with methylene chloride. The organic extract is washedwith saturated NaHCO₃, dried (Na₂ SO₄) and evaporated in vacuo to yieldthe crude product. Chromatography over 100 g of silica gel eluting with5% hexane/methylene chloride affords 1.16 g of the title compound as anoff white foam.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) 7.36, 7.07, 6.58, 6.54, 5.44, 5.24, 4.69, 4.61, 4.27,3.21, 3.01, 2.48, 1.90, 1.54, 1.15, 0.81, 0.76, 0.58 ppm

Anal. found: C, 76.62; H, 7.63; N, 4.17 α!_(D) (15.380 mg/2 mLCHCl₃)=+16°

PREPARATION 98

(3S)-3-1-(3-(Bis(phenylmethyl)amino)phenyl)propyl!-6,6-dipropyl-5,6-dihydro-4-hydroxy-2H-pyran-2-one(Formula W-11) Refer to Chart W

To 10 mL of dry tetrahydrofuran is added 770 mg of the title compound ofPreparation 97 (formula W-10) and the resulting solution cooled to 0° C.under an atmosphere of nitrogen. To that solution is added 150 mg of a60% oil dispersion of sodium hydride and the reaction is warmed to 20°C. and stirring continued for 16 hours. The reaction is quenched withsaturated ammonium chloride and extracted with ethyl acetate. Theextract is dried and evaporated in vacuo to yield the crude product.Chromatography over 100 g of silica gel eluting with 15% EtOAc/hexaneaffords 560 mg of the title product.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) 7.34, 6.69, 5.87, 4.69, 4.60, 4.09, 2.28, 2.17, 1.89,1.73, 1.55, 1.32, 0.88 ppm

Anal. found: C, 79.71; H, 8.07; N, 2.61!

α!_(D) (15.998 mg/2 mL CHCl₃)=-56°!

PREPARATION 99

(3S)-3-1-(3-aminophenyl)propyl!-6,6-dipropyl-5,6-dihydro-4-hydroxy-2H-pyran-2-one(Formula W-12) Refer to Chart W

The title compound of Preparation 98 (formula W-11) ((3R)-3-1-(3-bis-benzylaminophenyl)propyl!-6,6-bispropyl-5,6-dihydro-4-hydroxypyran-2-one)110 mg is added to 20 mL of ethyl acetate. To that solution is added 50mg of 10% Pd/C and the resulting mixture is hydrogenated at 50 psi for 6hours. The reaction is filtered through celite to yield 83 mg of thetitle product.

Physical characteristics are as follows:

IR 2957, 2922, 2855, 2871, 2854, 1378, 1605, 1459, 1617, 1262, 1319,1251, 1282, 1107 cm⁻¹.

α!_(D) (6.526 mg/2 mL CH₃ OH)=-34°

PREPARATION 100

(4R)3-(1-oxo-2-pentenyl)-4-phenyl-2-oxazolidinone (Formula X-4) Refer toChart X

A 2-L, three-necked, round-bottomed flask with nitrogen inlet andaddition funnel is charged with (R)-(-)-4-phenyl-2-oxazolidinone (31.2g) and tetrahydrofuran (1.2 L) and cooled to -78° C. The addition funnelis charged with n-butyllithium (1.6M in hexanes, 117 mL), which is addeddropwise to the reaction mixture over 20 min. A white precipitate isformed which is X-3. The reaction mixture is stirred for an additional30 min at -78° C. The addition funnel is then charged withtrans-2-pentenoyl chloride of formula X-2, prepared from the acid offormula X-1, (24.4 g) and tetrahydrofuran (50 mL), and this solution isadded to the reaction mixture dropwise over 10 min. The resulting paleyellow homogeneous solution is allowed to warm to room temperature andis stirred for another 30 min. The reaction mixture is quenched by theaddition of saturated ammonium chloride solution and is extracted withethyl acetate (2500 mL). The organic layer is separated, washed withbrine and water, dried over magnesium sulfate, filtered and concentratedto give 48 g of a white solid. The solid is recrystallized from ethylacetate (100 mL) and hexane (200 mL) to give 38.0 g the title product asa white solid.

Physical characteristics are as follows:

MP 86°-88° C.

¹ H NMR (CDCl₃) δ7.42-7.23, 7.18-7.09, 5.49, 4.70, 4.28, 2.28, 1.08 ppm.

IR (mineral oil) 1785, 1764, 1686, 1638, 1349, 1336, 1329, 1257, 1234,1214, 1087, 1076, 756, 716, 699 cm⁻¹

EI-MS: M+!=245.

PREPARATION 101

(3(3S),4R)-3- 3-(3-aminophenyl)-1-oxopentyl!-4-phenyl-2-oxazolidinone(Formula X-5) Refer to Chart X

A 2-L, three-necked, round-bottomed flask with nitrogen inlet andaddition funnel is charged with copper(I) bromide-dimethyl sulfidecomplex (25.1 g) and tetrahydrofuran (250 mL) and cooled to -40° C. Theaddition funnel is charged with 3-bis(trimethylsilyl)amino!phenylmagnesium chloride (1.0M in THF, 122 mL),which is added dropwise to the reaction mixture over 20 min. Thereaction mixture is then allowed to warm from -40° C. to -20° C. over 20min. The addition funnel is charged with 25 g of the title compound ofPreparation 100 (formula X-4) and tetrahydrofuran (100 mL), and thissolution is added to the reaction mixture dropwise over 30 min at 0° C.The reaction mixture is then stirred for 15 min at 0° C. and quenched bythe addition of saturated ammonium chloride solution (adjusted to pH 8by addition of ammonium hydroxide). The reaction mixture is poured intoether (2 L) and washed with the ammonium chloride solution until theaqueous layer is no longer blue in color. The organic layer isseparated, washed with water, dried over magnesium sulfate, filtered andconcentrated to give 58 g of a yellow oil. The crude reaction mixture isthen stirred at room temperature in a slurry of silica gel (75 g) andmethylene chloride (100 mL) for 1 h. The mixture is filtered, washedwith methanol, and concentrated to give 49 g of an oil. Columnchromatography on 300 g silica (eluting with 10-75% ethylacetate-hexane, 100% ethyl acetate) yields 30.9 g of a yellow oil. Theoil is crystallized from ethyl acetate (75 mL) and hexane (150 mL) togive 21.4 g of the title compound as a white solid.

Physical characteristics are as follows:

MP 94°-97° C.

¹ H NMR (CDCl₃) δ7.28-7.25, 7.07-6.99, 6.60-6.51, 5.38, 4.63, 4.16,3.52-3.44, 3.10-2.92, 1.65-1.53, 0.76 ppm.

IR (mineral oil) 3437, 3355, 1773, 1696, 1605, 1337, 1322, 1299, 1263,1212,1096, 1070, 791, 762, 704 cm⁻¹.

EI-MS: M+!=338.

PREPARATION 102

(3(3S),4R)-3-3-(3-(phenylmethyl)amino)phenyl)-1-oxopentyl!-4-phenyl-2-oxazolidinone(Formula X-6) Refer to Chart X

To a mixture of 80 mL of Na₂ CO₃ and 280 mL of methylene chloride isadded 21.0 g of (3(3S),4R)-3-3-(3-aminophenyl)-1-oxopentyl!-4-phenyl-2-oxazolidinone (formula X-5) ofPreparation 101 followed by 23.4 g of benzyl bromide. That mixture isheated at 65° C. for 18 hours, the methylene chloride layer separated,dried (Na₂ SO₄) and solvent evaporated to yield the crude product as adark viscous oil. The oil is chromatographed over 700 g of silica geleluding with 25% ethyl acetate/hexane to yield 31.42 g of the titlecompound.

Physical characteristics are as follows:

MP 91.8-93.5

¹ H NMR (CDCl₃) δ7.32, 7.08, 6.60, 5.34, 4.67, 4.15, 3.43, 3.02, 2.91,1.56, 0.65 ppm

PREPARATION 103

(3S)(4S)-3- 3-3-(Bis(phenylmethyl)amino!phenyl!-2-(2-methyl-1,3-dioxolan-2-yl!-1-oxopentyl!-4-phenyl-2-oxazolidinone(Formula X-8) Refer to Chart X

To 12 mL of methylene chloride, under nitrogen, is added 1.55 grams of(3(3S),4R)-3-3-(3-bisbenzylaminophenyl)pentanoyl!-4-phenyl-2-oxazolidinone (formulaX-6) of Preparation 102 and the resulting solution cooled to -78° C. Tothe aforementioned solution is added 646 μl of TiCl₄ followed by theaddition of 525 μl of diisopropylethylamine. After stirring at 0° C. for30 minutes the reaction is cooled back to -78° C. and 886 μl of2-methoxy-2-methyl-1,3-dioxolane (formula X-7) (also W-7) is added. Thereaction is stirred for 1 hour and then quenched by the addition ofsaturated NH₄ Cl, then saturated NaHCO₃ (pH 8) and finally extraction ofthe aqueous with both methylene chloride and ethyl ether. Evaporation ofsolvent affords a viscous oil which is chromatographed over 150 g ofsilica gel eluting with 7% hexane/methylene chloride to afford 1.14 g ofthe title compound.

Physical characteristics are as follows:

IR (mineral oil) 2920, 2954, 2854, 2870, 1776, 1376, 1453, 1196, 699cm⁻¹.

Anal. found: C, 75.27; H, 6.68; N, 4.55

PREPARATION 104

(3S)(4R) 3- 2-Acetyl-3- 3-bis(phenylmethyl)amino!phenyl!-1-oxopentyl!-4-phenyl-2-oxazolidinone(Formula X-9) Refer to Chart X

To 15 mL of THF is added 960 mg of (3(3S),4R)-3-2-(2-methyl-1,3-dioxan-2-yl)-3-(3-bisbenzylaminophenyl)pentanoyl!-4-phenyl-2-oxazolidinone(formula X-8) of Preparation 103. To that solution is then added 4 mL of30% perchloric acid and the resulting mixture stirred at 40° C. for 2hours. The reaction is cooled to room temperature and quenced with theaddition of excess saturated NaHCO₃. The reaction is extracted with 200mL of ethyl ether, dried (Na₂ SO₄) and solvent removed in vacuo to yield981 mg of the crude product. Chromatography over 100 g of silica geleluding with 10% pentane/methylene chloride affords 854 mg of the titlecompound.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.40, 7.08, 6.61, 6.56, 5.41, 4.96, 4.66, 4.61, 4.21,3.09, 1.63, 1.65, 0.61

IR (mineral oil) 1778, 1718, 1600, 1695, 1452, 1335, 1385, 1200 cm⁻¹.

EI-MS: M+!=560.

Anal. found: C, 76.81; H, 6.59; N, 4.84.

PREPARATION 105

(3S)(4R) 3- 2- 1- 3-bis(phenylmethyl)amino!phenyl!-propyl!-5-hydroxy-1,3-dioxo-5-propyloctyl!-4-phenyl-2-oxazolidinone(Formula X-10) Refer to Chart X

To 8 mL of methylene chloride under nitrogen is added 440 mg of(3(3S),4R)-3-2-(acetyl)-3-(3-bisbenzylaminophenyl)pentanoyl!-4-phenyl-2-oxazolidinone(formula X-9) of Preparation 104 and that solution is cooled to -78° C.To that solution is added 90 μl of TiCl₄ followed by the addition of 143μl of diisopropylethylamine. That solution is warmed to 0° C. for 40minutes and then cooled back to -78° C. at which time 126 μl of4-heptanone is added and the reaction temperature is elevated to 0° C.and stirring continued for 1.5 hours. The reaction is quenced with theaddition of saturated NH₄ Cl followed by the addition of saturatedNaHCO₃. The reaction is extracted with methlene chloride (3×60 mL),dried (Na₂ SO₄) and evaporated in vacuo to yield the crude product as anoil. That material is chromatographed over silica gel (100 g) elutingwith 10% pentane/methylene chloride to afford 293 mg of the titlecompound.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.28, 7.07, 6.56, 5.44, 5.24, 4.68, 4.61, 4.26, 3.21,3.10, 2.48, 1.90, 1.55, 1.21, 0.81, 0.74, 0.58

IR (mineral oil) 2959, 2931, 1779, 1720, 1690, 1600, 1494, 1452, 1385,1359, 1334, 1238, 698 cm⁻¹.

PREPARATION 106

(3R) 3- 1- 3-bis(phenylmethyl)amino!phenyl!propyl!-5,6-dihydro-4-hydroxy-6,6-dipropyl-2H-pyran-2-one(Formula X-11) Refer to Chart X

To 3 mL of THF was added 28 mg of NaH under nitrogen. To that suspensionis added 418 mg of (3(3S),4R)-3-2-((3-hydroxy-3-propyl)hexanoyl)-3-(3-bisbenzylaminophenyl)pentanoyl!-4-phenyl-2-oxazolidinone(Formula X-10) of Preparation 105 also in 3 mL of THF at 20° C. Thereaction is stirred for 16 hours, cooled to 0° C. and quenched byaddition of 1N HCl. The reaction is then made basic with the addition ofsaturated NaHCO₃. The aqueous is extracted several times with ethylacetate, the organic extracts dried (Na₂ SO₄) and solvent is removed invacuo to yield 518 mg of crude product. Chromatography over silica geleluting with 15% EtOAc/hexane affords 128 mg of the title compound.

Physical characteristics are as follows:

IR (mineral oil) 2959, 2931, 2873, 1636, 1599, 1451, 1465, 1386, 1363,1328, 1249, 1260, 696 cm⁻¹.

EI-MS: M+!=511.

PREPARATION 107

(3R) 3- 1- 3-amino!phenyl!propyl!-5,6-dihydro-4-hydroxy-6,6-dipropyl-2H-pyran-2-one(Formula X-12) Refer to Chart X

The dihydropyrone of formula X-11 ((3R)-3-1-(3-bisbenzylaminophenyl)-propyl!-6,6-bispropyl-5,6-dihydro-4-hydroxypyran-2-one)of Preparation 106, 110 mg, is added to 20 mL of ethyl acetate. To thatsolution is added 50 mg of 10% Pd/C and the resulting mixture ishydrogenated at 50 psi for 6 hours. The reaction is filtered throughcelite to yield 83 mg of the title product.

Physical characteristics are as follows:

IR (mineral oil) 2961, 2932, 2873, 1682, 1623, 1604, 1458, 1384, 1369,1319, 1282, 1259, 1150, 1108 cm⁻¹.

EI-MS: M+!=331

PREPARATION 108

2-Phenethyl-2-propen-1-ol (Formula BB-2) Refer to Chart BB

To a cooled (-10° C.) solution ofN,N,N,N,-tetramethyl-1,2-ethylenediamine (24.1 mL) in hexane (50 mL) isslowly added butyl lithium (100 mL of a 1.6M solution in hexane). Afterstirring for 45 minutes at -10° C. the mixture is cooled (-78° C.) and2-methyl-2-propen-1-ol (BB-1, 6.41 mL) is added dropwise. The reactionis allowed to warm to room temperature and stirred an additional 72 h.The mixture is cooled to -78° C. and a solution of benzyl bromide (8.6mL) in anhydrous THF (10 mL) is added slowly. The mixture is stirred at-78° C. for 1 hour then gradually allowed to warm to room temperature.After stirring an additional 2 hours, the reaction is quenched by theaddition of saturated aqueous NH₄ Cl. The organic layer is diluted withdiethyl ether and washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo. Purification by flash chromatography usingmethylene chloride/ethyl acetate/hexane (1:1:6) as eluent affords thetitle compound (3.5 g) as an oil.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.31-7.16, 5.07, 4.93, 4.09, 2.82-2.76, 2.41-2.36 ppm.

¹³ C NMR (CDCl₃) δ148.30, 141.69, 128.24, 125.80, 109.76, 65.90, 34.52,34.16 ppm.

PREPARATION 109

(2S)-2-Phenethyloxiranemethanol (Formula BB-8) Refer to Chart BB

To a cooled (-20° C.) slurry of molecular sieves (4 Å, crushed andfreshly activated, 150 mg) in methylene chloride (1.5 mL) is addeddiethyl L-tartrate (22 mg) and titanium(IV) isopropoxide (25 mg). Themixture is stirred for 30 min at -20° C. and tert-butyl hydroperoxide(0.84 mL of a 5-6M solution in nonane) is added. After an additional 25min at -20° C., a solution of allylic alcohol of formula BB-2 (300 mg)of Preparation 108 in methylene chloride (0.5 mL) is slowly added. Themixture is stirred overnight at -20° C. then warmed to -10° C. After anadditional 4 hours the reaction is warmed to 0°-5° C. and quenched withthe addition of water (1 mL). After warming to room temperature,stirring is continued for 1 hour and tartrates hydrolysed by theaddition of a 30% aqueous NaOH solution saturated with NaCl (0.1 mL).After 30 minutes, the mixture is filtered through Celite and the aqueousphase extracted with several portions of methylene chloride. Thecombined organic layers are dried (MgSO₄), filtered and concentrated invacuo to provide a residue which is purified by flash chromatographyusing hexane and a gradient of ethyl acetate (10-20%) as eluent toafford the title product of formula BB-3 (223 mg) as an oil. Theenantiomeric excess of the reaction is determined to be 86% by analysisof the ¹ H NMR (C₆ D₆) of the Mosher ester formed by the reaction ofBB-3 with (S)-(+)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride (J.A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem. (1969) 34:2543).

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.34-7.16, 3.83-3.61, 2.89-2.87, 2.72-2.64, 2.17-2.04,1.89-1.79 ppm

¹³ C NMR (CDCl₃) δ141.17, 137.58, 128.49, 128.21, 126.11, 63.00 59.57,49.92, 33.58, 30.82 ppm.

PREPARATION 110

(2S)-2-Phenethyl-2-phenylmethoxymethyloxirane (Formula BB-9) Refer toChart BB

To a cooled (0°-5° C.) slurry of sodium hydride (124 mg of a 60%suspension in mineral oil) in THF (10 mL) is added alcohol of formulaBB-3 (460 mg) of Preparation 109. The mixture is stirred at 0°-5° C. for5 minutes, allowed to warm to room temperature and stirred an additional30 minutes. Benzyl bromide (441 mg) is added and the mixture stirred atroom temperature overnight. The mixture is quenched with brine (10 mL)and diluted with ethyl ether. The organic layer is washed with brine,dried (MgSO₄), filtered and concentrated in vacuo to provide a residuewhich is purified by flash chromatography using hexane and a gradient ofethyl acetate (2-5%) as eluent to afford the title product (510 mg) asan oil.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.34-7.13, 4.59-4.49, 3.64-3.45, 2.75-2.59, 2.19-2.09,1.94-1.84

¹³ C NMR (CDCl₃) δ141.42, 137.93, 128.58, 128.38, 127.88, 125.94, 73.23,71.98, 58.21, 50.37, 33.65, 30.83 ppm.

PREPARATION 110a

(3S)-1-Phenyl-3-(phenylmethoxymethyl) hexan-3-ol (Formula BB-10) Referto Chart BB

To a cooled (-45° C.) solution of Li₂ CuCl₄ (0.28 mL of a 0.1M solutionin THF) in THF (2 mL) is added ethylmagnesium bromide (0.203 mL of a 3Msolution in ethyl ether). The brown solution is stirred at -45° C. for45 minutes and the epoxide of formula BB-4 (150 mg) of Preparation 110is added dropwise over ca. 10 minutes. After one hour the reaction isquenched by the addition of saturated aqueous NH₄ Cl and the aqueouslayer extracted with ethyl acetate. The combined organic layers arewashed with brine, dried (MgSO₄), filtered and concentrated in vacuo toprovide a residue which is purified by flash chromatography usinghexane/ethyl acetate (5%) as eluent to afford the title product (150 mg)as an oil.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.38-7.14, 4.54, 3.37, 2.66-2.58, 2.20, 1.88-1.76,1.58-1.52, 1.39-1.25, 0.92

¹³ C NMR (CDCl₃) δ142.61, 138.10, 128.41, 128.33, 127.71, 127.63,125.68, 75.45, 73.79, 73.44, 38.95, 38.52, 29.86, 16.79, 14.37 ppm.

PREPARATION 110b

(2R)-2-Phenethyl-2-(p-toluenesulfonyloxymethyl) oxirane (Formula BB-13)Refer to Chart BB

To a cooled (ca. -10° C.) solution of the compound of formula BB-8 (245mg) of Preparation 109 in methylene chloride (4 mL) is added4-toluenesulfonyl chloride (302 mg), triethylamine (160 mg) and4-dimethylaminopyridine (8 mg). The mixture is stirred at ca. -10° C.overnight then warmed to 0°-5° C. for 1 hour. The mixture is dilutedwith methylene chloride, washed with saturated aqueous NaHCO₃ and brine,dried (MgSO₄), filtered and concentrated in vacuo to provide a residuewhich is purified by flash chromatography using hexane/ ethyl acetate(5%) as eluent to afford the title compound (448 mg).

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.79, 7.33, 7.28-7.08, 4.13-3.98, 2.64-2.58, 2.44,2.11-2.00, 1.92-1.82

¹³ C NMR (CDCl₃) δ145.17, 140.67, 132.53, 129.96, 128.48, 128.19,127.95, 126.15, 71.98, 56.49, 50.63, 32.89, 30.37, 21.64 ppm.

PREPARATION 110c

(2S)-2-Phenethyl-2-propyl oxirane (Formula BB-12) Refer to Chart BB

To a cooled (-45° C.) solution of Li₂ CuCl₄ (0.3 mL of a 0.1M solutionin THF) in THF (2 mL) is added ethylmagnesium bromide (0.22 mL of a 3Msolution in ethyl ether). The brown solution is stirred at -45° C. for45 minutes, cooled to -65° C. then tosylate of formula BB-13 (200 mg) ofPreparation 110b is added dropwise over ca. 10 minutes. The mixture isstirred for 2.5 hours, warmed to -50° C. for 2 hours and then quenchedby the addition of saturated aqueous NH₄ Cl. The aqueous layer isextracted with ethyl acetate and the combined organic layers washed withbrine, dried (MgSO₄), filtered and concentrated in vacuo to provide aresidue which is purified by flash chromatography using hexane/ethylacetate (5%) as eluent to afford the title product (60 mg) andhydroxytosylate of formula BB-14 (47 mg).

Hydroxytosylate of formula BB-14 is converted to the epoxide of formulaBB-12 as follows: To a cooled (0°-5° C.) solution of the compound offormula BB-14 (43 mg) in methanol (2 mL) is added anhydrous K₂ CO₃ (20mg). After 1 hour at 0°-5° C. the mixture is warmed to room temperature,stirred an additional 90 minutes then quenched by the addition ofsaturated aqueous NH₄ Cl. The aqueous layer is extracted with ethylacetate and the combined organic layers washed with brine, dried(MgSO₄), filtered and concentrated in vacuo to provide a residue whichis purified by flash chromatography using hexane/ethyl acetate (5%) toafford the epoxide of formula BB-12 (20 mg).

Physical characteristics for BB-12 are as follows:

¹ H NMR (CDCl₃) δ7.31-7.16, 2.68, 2.59, 1.98-1.82, 1.73-1.37, 0.94

¹³ C NMR (CDCl₃) δ141.71, 128.41, 128.24, 125.92, 59.11, 52.57, 36.42,36.02, 31.03, 18.19, 14.22 ppm.

Physical characteristics for BB-14 are as follows:

¹ H NMR (CDCl₃) δ7.79, 7.34, 7.29-7.11, 3.90, 2.58-2.53, 2.44, 1.87,1.77-1.72, 1.54-1.48, 1.31-1.21, 0.89

¹³ C NMR (CDCl₃) δ145.10, 141.66, 132.50, 129.97, 128.45, 128.25,127.97, 125.96, 74.33, 73.07, 38.37, 37.87, 29.37, 21.66, 16.47, 14.48ppm.

PREPARATION 111

(4S)-3-acetyl-4-phenyl-2-oxazolidinone (Formula FF-3) Refer to Chart FF

To a solution of (S)-(+)-4-phenyl-2-oxazolidinone of formula FF-2 (20 g)in anhydrous tetrahydrofuran (600 mL), cooled to -78° C. is added asolution of 1.6M n-butyllithium in hexanes (77.8 mL) and the resultingsuspension stirred at -78° C. for 30 minutes. The suspension is treatedwith acetyl chloride of formula FF-1 (10.23 mL) and then graduallyallowed to warm to room temperature. The reaction mixture is quenchedwith 1 L of saturated ammonium chloride and then partitioned betweenwater and ethyl acetate. The organic layer is separated and the aqueouslayer reextracted twice with ethyl acetate. The combined organic layersare washed with brine, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The crude solid is recrystallized from ethylacetate/hexane affording (21.27 g,) as a white solid.

Physical Characteristics are as follows:

Mp 86°-87° C.

¹ H NMR (CDCl₃) δ7.42-7.26, 5.44-5.40, 4.68, 4.30-4.26, 2.52 ppm

¹³ C NMR (CDCl₃) δ169.50, 153.71, 138.81, 128.97, 128.53, 125.73, 69.73,57.20, 23.59 ppm

PREPARATION 112

(3(2E),4S)-3- 4,4-dimethyl (2-pentenoyl)!-4-phenyl-2-oxazolidinone(Formula FF-4) Refer to Chart FF

To a solution of the compound of formula FF-3 of Preparation 111 (21.27g) in anhydrous methylene chloride (500 mL), cooled to -78° C., is addedtitanium tetrachloride (12.0 mL) in a dropwise manner. The suspension istreated with diisopropylethylamine (19.9 mL) and is allowed to stir at-78° C. for 30 minutes. The suspension is then treated withtrimethylacetaldehyde (11.4 mL) followed by diisopropylethylamine (19.9mL) and allowed to gradually warm to room temperature. After 1 hour thereaction mixture is quenched with water (200 mL) and stirred vigorouslyfor 15 minutes. The organic layer is separated and the aqueous layer isreextracted with methylene chloride. The combined organic layers arewashed with brine, dried over anhydrous sodium sulfate, and concentratedin vacuo. The crude solid is recrystallized from ethyl acetate/hexaneaffording 21.6 grams of the title compound as a off-white solid:

Physical characteristics are as follows:

Mp 148°-149° C.

¹ H NMR (CDCl₃) δ7.42-7.05 , 5.51-5.46, 4.69, 4.30-4.25, 1.09 ppm

¹³ C NMR (CDCl₃) δ165.17, 161.61, 153.70, 139.16, 129.12, 128.61,125.97, 115.71, 69.88, 57.74, 34.31, 28.56 ppm;

PREPARATION 113

(3(3S),4S)-3-3-(3-Aminophenyl)-4,4-dimethylpentanoyl!-4-phenyl-2-oxazolidinone(Formula FF-5) Refer to Chart FF

To a slurry of copper(I) bromide dimethylsulfide complex (18.76 g) inanhydrous tetrahydrofuran (60 mL), cooled to -78° C., is added a 1.0Msolution of 3- bis(trimethylsilyl)amino!phenylmagnesium chloride intetrahydrofuran (182.2 mL) and the resulting slurry stirred at -78° C.for 5 minutes. The slurry is allowed to warm to -15° C. for 15 minutesand then cooled to -78° C. The slurry is then treated with the compoundof formula FF-4 of Preparation 112 (16.6 g) added via a solid additionfunnel and allowed to stir at -78° C. for 3 hours. The reaction mixtureis poured into saturated ammonium chloride (200 mL) and then partitionedbetween water and ethyl acetate. The organic layer is separated and theaqueous layer (pH 8) is basified to pH 9.5 with concentrated ammoniumhydroxide. The aqueous layer is reextracted three times with ethylacetate, the combined organic layers are washed with brine, dried overanhydrous sodium sulfate, and concentrated in vacuo. The crude residueis slurried in chloroform (400 mL) and 200 g of silica gel (230-400mesh) at room temperature for 2 hours. The slurry is filtered and thesolids washed several times with chloroform followed by methanol. Thefiltrate is concentrated in vacuo. Purification by flash chromatographyeluting with hexane/ethyl acetate (15-40%) afford 17.52 grams of thetitle compound as a light yellow solid.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.26-7.12, 7.01, 6.74-6.70, 6.61-6.50, 5.32-5.28, 4.56,4.11-3.95, 3.48, 2.97-2.91, 0.91 ppm

¹³ C NMR (CDCl₃) δ172.34, 153.51, 145.37, 142.24, 138.12, 128.67,128.23, 127.68, 124.71, 119.80, 116.49, 113.02, 69.39, 57.39, 52.30,34.75, 33.49, 27.83 ppm

PREPARATION 114

(3(3S),4S)-3-3-(3-Bisbenzylaminophenyl)-4,4-dimethylpentanoyl!-4-phenyl-2-oxazolidinone(Formula FF-6) Refer to Chart FF-6

To a solution of the compound of formula FF-5 of Preparation 113 (15.0g) in methylene chloride (190 mL) at room temperature is added saturatedsodium carbonate (48.7 mL) followed by benzyl bromide (14.3 mL) and theresulting mixture is refluxed for 24 hours. The reaction mixture isallowed to cool to room temperature and partitioned between water (300mL) and methylene chloride. The organic layer is separated, washed withbrine, dried over anhydrous sodium sulfate, and concentrated in vacuo.Purification by flash chromatography eluting with hexane/ethyl acetate(10-25%) affords 15.1 grams of the title compound as a white solid.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.29-6.99, 6.69-6.49, 5.32-5.26, 4.71-4.50, 4.06-3.94,2.90-2.81, 0.73 ppm

¹³ C NMR (CDCl₃) δ172.79, 153.78, 148.32, 142.08, 139.04, 138.48,129.07, 128.59, 128.37, 127.89, 126.83, 124.92, 118.44, 114.64, 110.87,69.70, 57.68, 54.77, 52.97, 34.84, 33.79,27.97 ppm

PREPARATION 115

S, R*,S*(E)!!-N-(2-hydroxy-1-methyl-2-phenylethyl)-methyl-N-pentenamide(Formula NNN-3) See Chart NNN

A 250-mL, three-necked, round-bottomed flask with nitrogen inlet andaddition funnel is charged with the compound of formula NNN-1 (6.6 g)(prepared from the treatment of commercially available trans-2-pentenoicacid with oxalyl chloride) and tetrahydrofuran (80 mL). The additionfunnel is charged with a solution of (1R,2S)-ephedrine of formula NNN-2(7.2 g) and triethylamine (6.0 mL) in tetrahydrofuran (15 mL), which isadded dropwise to the reaction mixture. After stirring an additionalhour, the reaction mixture is poured into 200 mL of ethyl acetate,washed with three 25-mL portions of water, and concentrated in vacuo toyield 13.5 g of an oil. Column chromatography on 100 g silica (elutionwith 10-100% ethyl acetate-hexane) yields 10.75 g of the title compoundas a colorless oil.

Physical characteristics are as follows:

HRMS found: 248.1652.

PREPARATION 116

1R-1R*(R*)2S*!!-3-Amino-β-ethyl-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl-benzenepropanamide(Formula NNN-4) See Chart NNN

A 50-mL, three-necked round-bottomed flask with a nitrogen inlet ischarged with the title compound of Preparation 115 (0.247 g) and 5 mL oft-butyl methyl ether and cooled to 0° C. Propyl magnesium chloride (0.55mL of 2.0M solution in ether) is added dropwise, and the reactionmixture is stirred for an additional 15 min. 3-Bis(trimethylsilyl)amino!phenylmagnesium chloride (2.0 mL of 1.0Msolution in tetrahydrofuran, 2.0 mmol) is added dropwise, and theresulting mixture is stirred for an additional 2 h at 0° C. and 1 h atroom temperature. The reaction mixture is then quenched with saturatedaqueous ammonium chloride solution (pH adjusted to 8 with ammoniumhydroxide) and partitioned between 100 mL of ethyl acetate and 5 mL ofwater. The organic layer is separated, washed with additional ammoniumchloride solution and water, and concentrated in vacuo to give 0.72 g ofa yellow oil. The crude oil is then dissolved in chloroform, and silicagel is added to the solution. The resulting mixture is stirred at roomtemperature for 1.5 h, then filtered through Celite, rinsing withmethanol, and concentrated in vacuo to give 0.38 g of a yellow oil.Column chromatography on 50 g of silica gel (elution with 20-100% ethylacetate-hexane) yields 0.174 g of the title compound as an oil.

Physical characteristics are as follows:

HRMS found: 340.2162.

PREPARATION 117

1R- 1R*(R*)2S*!!-3-bis(phenylmethyl)amino!-b-ethyl-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl-benzenepropanamide(Formula NNN-5) See Chart NNN

A 50-mL, three-necked, round-bottomed flask with a condenser fitted witha nitrogen inlet is charged with the title product of Preparation 116(0.548 g) in 8 mL of acetonitrile. Sodium carbonate (0.375 g) and benzylbromide (0.42 mL) are added, and the reaction mixture is heated toreflux for 4 h. The reaction mixture is then concentrated in vacuo andpartitioned between 100 mL of ethyl acetate and 10 mL of water. Theorganic layer is separated, washed with another 10 mL of water, andconcentrated in vacuo to give 1.0 g of a yellow oil. Columnchromatography on 65 g of silica gel (elution with 20-100% ethylacetate-hexane and 5% methanol-methylene chloride) yields 0.447 g of thetitle compound as a pale yellow oil.

Physical characteristics are as follows:

HRMS found: 520.3102.

PREPARATION 118

1-phenyl-6,6,6-trifluoro-3-hexanol (Formula PPP-2) Refer to Chart PPP

To a stirred solution of 4.0 g of ethyl 4,4,4-trifluorobutyrate offormula PPP-1 in 25 mL of tetrahydrofuran at -70° C. 24 mL of DiBAL-H(1M in toluene) is added dropwise and the solution stirred for 90 min.In a separate flask containing 680 mg of magnesium turnings and 5 mL oftetrahydrofuran is added 1-phenyl-2-bromoethane in 20 mL oftetrahydrofuran at a rate to maintain reflux. Heating of the mixture iscontinued for an additional 1 h, then cooled to room temperature andadded via cannula to the DiBAL-H reaction above. The resulting whitesuspension is stirred 30 min at -70° C. and then allowed to warm to roomtemperature. The reaction is quenched with saturated aqueous ammoniumchloride, diluted with 1N hydrochloric acid to dissolve the precipitatedsalts and extracted with ethyl acetate. The organic layers are combined,washed with water and brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude product is flashchromatographed on silica gel eluting with 20% ethyl acetate in hexaneto give 2.0 g of the title compound as a colorless oil.

Physical characteristics are as follows:

HRMS: 232.1088

IR (neat liquid): 3385, 2950, 1455, 1255, 1140, 700 cm⁻¹.

PREPARATION 119

1-phenyl-6,6,6-trifluoro-3-hexanone (Formula PPP-3) Refer to Chart PPP.

To a solution of 0.48 mL of oxalyl chloride in 10 mL of dichloromethaneat -60° C. is added dropwise 0.81 mL of dimethylsulfoxide. The solutionis stirred for 5 min then treated with 860 mg of1-phenyl-6,6,6-trifluoro-3-hexanol of formula PPP-2 of Preparation 118in 5 mL of dichloromethane and stirred for 15 min. Triethylamine (1.5mL) is added, the mixture is allowed to warm to room temperature,diluted with water and the layers separated. The aqueous layer isextracted with dichloromethane, the organic layers combined, dried overanhydrous sodium sulfate, filtered, and concentrated. The resulting oilis flash chromatographed on silica gel to give 600 mg of the titlecompound as an oil.

Physical characteristics are as follows:

¹ H NMR (CDCl₃): δ7.2-7.3, 2.9, 2.7, 2.6, 2.4.

¹³ C NMR (CDCl₃): δ206, 140, 129, 128, 126, 125, 44, 35, 30, 28.

PREPARATION 120

5,6-dihydro-4-hydroxy-6-phenethyl-6-(3',3',3'-trifluoropropyl)-2H-pyran-2-one(Formula PPP-4) Refer to Chart PPP

A suspension of 350 mg of 50% sodium hydride in 10 mL of tetrahydrofuranat 0° C. is treated dropwise with 0.78 mL of methyl acetoacetate. Afterstirring 30 min, 4.5 mL of 1.6M n-butyllithium in hexane is added andstirring continued for 15 min. A solution of 840 mg of1-phenyl-6,6,6-trifluoro-3-hexanone in 5 mL of tetrahydrofuran offormula PPP-3 of Preparation 119, is added, stirred at 0° C. for 15 min,then allowed to warm to room temperature and stirred for 1 h. Thereaction mixture is quenched with saturated aqueous ammonium chlorideand extracted with ethyl acetate. The organic layers are washed withwater and brine, concentrated in vacuo, then dissolved in 20 mL oftetrahydrofuran. The solution is diluted with 60 mL of water and treatedwith 20 mL of 1N sodium hydroxide, stirred for 3 h at room temperature,concentrated in vacuo to remove the tetrahydrofuran, cooled to 5° C.,and acidified with concentrated hydrochloric acid. The mixture isextracted with dichloromethane, dried over anhydrous sodium sulfate,filtered and concentrated. The crude material is flash chromatographedon silica gel eluting with 30% ethyl acetate in hexane to give 870 mg ofthe title compound.

Physical characteristics are as follows:

ANAL: C, 61.14, H, 5.45.

PREPARATION 121

3- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl-carbamicacid, phenylmethylester (Formula QQQ-3 where R₁ =t-Bu) Refer to ChartQQQ

The title compound of Preparation 120 (850 mg) in 25 mL oftetrahydrofuran at 0° C. is treated with 750 mg of aluminum trichloride,stirred 15 min, and then 700 mg of 3-benzyloxycarbonylaminobenzaldehydeis added. The mixture is allowed to stir at room temperature for 2 hthen treated with 2 g of sodium carbonate monohydrate and 0.1 mL ofwater, stirred for 30 min, and filtered through celite washing thefilter cake with tetrahydrofuran. The filtrate is concentrated in vacuo.The resulting material is dissolved in 25 mL of tetrahydrofuran and 285mg of cuprous bromide-dimethylsulfide complex is added and the mixturestirred for 15 min before adding 11 mL of 1M t-butylmagnesium bromide intetrahydrofuran dropwise over 15-20 min. The resulting brown mixture isstirred an additional 15 min then quenched at 0° C. with 50 mL of water.The layers are separated and the aqueous layer acidified withconcentrated hydrochloric acid to dissolve inorganic salts and thenextracted with ethyl acetate. The combined organic layers are washedwith water and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography on silica gel eluting withethyl acetate in hexane gives 1.19 g of the title compound as a white tobuff colored foam.

Physical characteristics are as follows:

¹ H NMR (CDCl₃): δ7.1-7.7, 6.7, 6.5, 4.4, 1.8-2.8, 1.16.

HRMS: 609.2711.

PREPARATION 122

Preparative resolution of 3- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl-carbamicacid, phenylmethylester (Formula QQQ-3 where R₁ =t-Bu) into 4 isomers,3(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6-(R or S)-(2-phenethyl)-6-(RorS)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethyl-propyl!phenyl-carbamicacid, phenylmethylester (Formulas QQQ-4-7 where R₁ is t-Bu) Refer toChart QQQ

The first phase of the resolution is accomplished with a 5.1×25 cm(R,R)Whelk-O 1 column eluted with 15% (V/V) isopropanol in hexane at 99mL/min. ((R,R)Whelk-O 1 is a registered trademark of Regis Technologies,Inc., Morton Grove, Ill. 60053.) The peaks eluting at approximately 54and 87 min are, respectively, pure Isomer 3 and Isomer 2 as judged fromSystem A, below. The mixture of unresolved Isomer 1 and Isomer 4 elutedat approximately 64 minutes and is further treated as described below.

In the second phase of the resolution, the mixture from above thatelutes near 64 minutes is injected onto a 2.1×25 cm Chiralcel OD column(Chiral Technologies, Inc.) and eluted with 35% isopropanol in hexane(V/V) at 8 mL/min. The peaks that elute near 8.7 and 23.9 minutes are,respectively, Isomer 1 and Isomer 4.

In both phase of the resolution of enantiomers, fractions are pooledafter assay with System A and pools are concentrated to dryness on arotary evaporator at 30 mm and a bath set at 50° maximum.

The four constituent enantiomers are (in order of elution from system A)designated (Peak #1), (Peak #2), (Peak #3) and (Peak #4). System Aconsists of a 0.46×25 cm Chiralcel OD-H column eluted at 1.0 mL/min with20% isopropanol in hexane (V/V). (Chiralcel OD-H is a registeredtrademark of Chiral Technologies, Inc., Exton Pa. 19341.)

PREPARATION 123

3(R or S)-1-(3-aminophenyl)-2,2-dimethylpropyl!-4-hydroxy-5,6-dihydro-6-(R orS)-phenethyl-6-(3,3,3-trifluoropropyl)-2H-pyran-2-one (Formula QQQ-8, R₁=t-Bu) Refer to Chart QQQ

A solution of 210 mg of the compound identified as peak 1 fromPreparation 122 in 10 mL of methanol is treated with 400 mg of ammoniumformate and 40 mg of 10% palladium on charcoal, stirred 2 h, filteredthrough celite washing the filter cake with methanol. The filtrate isdiluted with ethyl acetate and washed with water and brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give 160mg of the title compound as a white foam.

Physical characteristics are as follows:

¹ H NMR (CD₃ OD): δ6.9-7.3, 6.6, 4.1, 2.6-2.7, 1.9-2.4, 1.0.

TLC (silica gel GF): R_(f) =0.24 (40% ethyl acetate in hexane).

EXAMPLE 266

5-cyano-N- 3-(R or S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R orS)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide(Formula QQQ-13, R₁ is t-Bu R₂ is 5-cyano-2-pyridinyl!) Refer to ChartQQQ

A solution of the title product of Preparation 123 (50 mg), pyridine (30mL), and 5-cyano-pyridine-2-sulfonyl chloride (30 mg) in dichloromethaneat 0° C. is stirred for 2 h. The crude reaction mixture ischromatographed on silica gel to give the title compound as a whiteamorphous solid.

Physical characteristics are as follows:

FAB HRMS: 642.2267.

EXAMPLE 267

N- 3-(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6-(R orS)-(2-phenethyl)-6-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula QQQ-13, R₁ is t-Bu, R₂ is 1-methyl-4-imidazolyl!) Refer toChart QQQ

Following the procedure described in EXAMPLE 266 and substituting5-cyano-2-pyridine sulfonyl chloride with 1-methylimidazole-4-sulfonylchloride the title compound is prepared.

Physical characteristics are as follows:

HRMS: 619.2298

EXAMPLE 268

5-amino-N- 3-(R or S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R orS)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide(Formula QQQ-13, R₁ =t-Bu, R₂ is 5-amino-2-pyridinyl!) Refer to ChartQQQ

A solution of the title product of Preparation 123 (50 mg), pyridine (30μL), and 5-nitro-pyridine-2-sulfonyl chloride (30 mg) in dichloromethaneat 0° C. is stirred for 2 h. The crude reaction mixture ischromatographed on silica gel to give the sulfonamide as a whiteamorphous solid. The white solid is dissolved in 4 mL of methanol andtreated with 25 mg of ammonium formate and 5 mg of 10% palladium oncarbon, stirred for 1 h at room temperature, diluted with water andextracted with dichloromethane, dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to give the title compound as anoff-white amorphous solid.

Physical characteristics are as follows:

FAB HRMS: 632.2393.

PREPARATION 124

3(R or S)-1-(3-aminophenyl)-2,2-dimethyl-propyl!-4-hydroxy-5,6-dihydro-6(S orR)-phenethyl-6-(3',3',3'-trifluoropropyl)-2H-pyran-2-one (Formula QQQ-9,R₁ is t-Bu!) Refer to Chart QQQ

Following the procedure described in Preparation 123 beginning with thecompound isolated from peak 2 from Preparation 122 and using startingmaterials and reagents known and available to one of ordinary skill inorganic synthesis the title compound is prepared.

Physical characteristics are as follows: 1H NMR (CD₃ OD): δ6.9-7.3, 6.6,4.1, 2.6-2.7, 1.9--2.4, 1.0.

TLC (silica gel GF): R_(f) =0.24 (40% ethyl acetate in hexane).

EXAMPLE 269

5-cyano-N- 3-(R or S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R orS)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide(Formula QQQ-14, R₁ is t-Bu R₂ is 5-cyano-2-pyridinyl!) Refer to ChartQQQ

A solution of the title product of Preparation 124 (50 mg), pyridine (30μL), and 5-cyanopyridine-2-sulfonyl chloride (30 mg) in dichloromethaneat 0° C. is stirred for 2 h. The crude reaction mixture ischromatographed on silica gel to give the title compound as a whiteamorphous solid.

Physical characteristics are as follows:

FAB HRMS: 642.2260.

EXAMPLE 270

N- 3-(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6-(R orS)-(2-phenethyl)-6-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula QQQ-14, R₁ is t-Bu R₂ is 1-methyl-4-imidazolyl!) Refer to ChartQQQ

Following the procedure described in Example 266 substituting5-cyano-2-pyridine sulfonyl chloride with 1-methylimidazole-4-sulfonylchloride the title compound is prepared.

Physical characteristics are as follows:

HRMS: 619.2362

EXAMPLE 271

5-amino-N- 3-(R or S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R orS)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide(Formula QQQ-14, R₁ is t-Bu R₂ is 5-amino-2-pyridinyl!) Refer to ChartQQQ

Following the procedure described in Example 268 the title compound isprepared.

Physical characteristics are as follows:

FAB HRMS: 632.2387

PREPARATION 125

3-(S or R)-1-(3-aminophenyl)-2,2-dimethyl-propyl!-4-hydroxy-5,6-dihydro-6-(R orS)-phenethyl-6-(R or S)-(3',3',3'-trifluoropropyl)-2H-pyran-2-one(Formula QQQ-10 R₁ is t-Bu!) Refer to Chart QQQ

Following the procedure described in Preparation 123 beginning with thecompound isolated from peak 3 from Preparation 122 and using startingmaterials and reagents known and available to one of ordinary skill inorganic synthesis the title compound is prepared.

Physical characteristics are as follows:

¹ H NMR (CD₃ OD): δ6.9-7.3, 6.6, 4.1, 2.6-2.7, 1.9-2.4, 1.0.

TLC (silica gel GF): R_(f) =0.24 (40% ethyl acetate in hexane).

EXAMPLE 272

5-cyano-N- 3-(R or S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R orS)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide(Formula QQQ-15, R₁ is t-Bu, R₂ is 5-cyano-2-pyridinyl!) Refer to ChartQQQ

A solution of the title product of Preparation 125 (50 mg), pyridine (30mL), and 5-cyanopyridine-2-sulfonyl chloride (30 mg) in dichloromethaneat 0° C. is stirred for 2 h. The crude reaction mixture ischromatographed on silica gel to give the title compound as a whiteamorphous solid.

Physical characteristics are as follows:

FAB HRMS: 642.2254

EXAMPLE 273

N- 3-(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6-(R orS)-(2-phenethyl)-6-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula QQQ-15, R₁ is t-Bu, R₂ is 1-methyl-4-imidazolyl!) Refer toChart QQQ

Following the procedure described in Example 266 substituting5-cyano-2-pyridine sulfonyl chloride with 1-methylimidazole-4-sulfonylchloride the title compound is prepared.

Physical characteristics are as follows:

FAB HRMS: 642.2397

EXAMPLE 274

5-amino-N- 3-(R or S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R orS)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide(Formula QQQ-15, R₁ is t-Bu R₂ is 5-amino-2-pyridinyl!) Refer to ChartQQQ

Following the procedure described in Example 268 the title compound isprepared.

Physical characteristics are as follows:

FAB HRMS: 632.2393

PREPARATION 126

3-(S or R)-1-(3-aminophenyl)-2,2-dimethyl-propyl!-4-hydroxy-5,6-dihydro-6 (S orR)-phenethyl-6-(3',3',3'-trifluoropropyl)-2H-pyran-2-one (Formula QQQ-11R₁ is t-Bu!) Refer to Chart QQQ

Following the procedure described in Preparation 123 beginning with thecompound isolated from peak 4 from Preparation 122 and using startingmaterials and reagents known and available to one of ordinary skill inorganic synthesis the title compound is prepared.

Physical characteristics are as follows:

¹ H NMR (CD₃ OD): δ6.9-7.3, 6.6, 4.1, 2.6-2.7, 1.9-2.4, 1.0.

TLC (silica gel GF): R_(f) =0.24 (40% ethyl acetate in hexane)

EXAMPLE 275

5-cyano-N- 3-(R or S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R orS)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide(Formula QQQ-16, R₁ is t-Bu, R₂ is 5-cyano-2-pyridinyl!) Refer to ChartQQQ

A solution of the title product of Preparation 126 (50 mg), pyridine (30mL), and 5-cyanopyridine-2-sulfonyl chloride (30 mg) in dichloromethaneat 0° C. is stirred for 2 h. The crude reaction mixture ischromatographed on silica gel to give the title compound as a whiteamorphous solid.

Physical characteristics are as follows:

FAB HRMS: 642.2248.

EXAMPLE 276

N- 3-(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6-(R orS)-(2-phenethyl)-6-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula QQQ-16, R₁ is t-Bu, R₂ is 1-methyl-4-imidazolyl!) Refer toChart QQQ

Following the procedure described in Example 266 substituting5-cyano-2-pyridine sulfonyl chloride with 1-methylimidazole-4-sulfonylchloride the title compound is prepared.

Physical characteristics are as follows:

FAB HRMS: 620.2403

EXAMPLE 277

5-amino-N- 3-(R or S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R orS)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide(Formula QQQ-16, R₁ is t-Bu, R₂ is 5-amino-2-pyridinyl!) Refer to ChartQQQ

Following the procedure described in Example 268 the title compound isprepared.

Physical characteristics are as follows:

FAB HRMS: 632.2406

EXAMPLE 278

N- 3-(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)- 6-(R orS)-propyl!-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide

Following procedures analogous to those described above and using Isomer2 of Preparation 143 the title compound is prepared.

Physical characteristics are as follows:

FAB HRMS: 562.2527.

EXAMPLE 279

N- 3-(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R orS)-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide

Following procedures analogous to those described above and using Isomer1 of Preparation 143 the title compound is prepared.

Physical characteristics are as follows:

FAB HRMS: 562.2528.

PREPARATION 127

2-Mercapto-4-trifluoromethylpyridine

To 1.0 g of 2-chloro-4-trifluoromethylpyridine (Lancaster Chemical Co)is added 10 ml of absolute ethanol and 417 mg of thiourea. The reactionmixture is heated at reflux for 4 hours and 1.25 ml of a solution of7.44 g KOH in 20 ml of water is added. The solution is heated at refluxfor an additional 1 hour. The reaction solution is cooled and pouredinto 100 ml of a 0.1N NaOH solution. The resulting solution is extractedthree times with 100 ml of methylene chloride and the resulting aqueoussolution is acidified to pH 4 by addition of glacial acetic acid. Theaqueous solution is extracted three times with 100 ml of methylenechloride and the organic solution is dried over anhydrous sodiumsulfate. Filtration followed by evaporation to dryness gives 501 mg of ayellow crystalline solid.

Physical characteristics are as follows:

Found C:40.22; H:2.33; N:8.07; S:17.59

HRMS: 179.0019

PREPARATION 128

2-Chlorosulfonyl-4-trifluoromethylpyridine

To 425 mg of 2-mercapto-4-trifluoromethylpyridine of Preparation 127 isadded 10 ml of 1N aqueous HCl. The reaction mixture is cooled to 0° C.and Cl₂ gas is bubbled into the cold reaction mixture for 15 minutes.The reaction mixture is filtered and the resulting solid is washed wellwith water. The white solid is dissolved in methylene chloride and iswashed twice with saturated aqueous NaHCO₃ followed by one wash withwater. After drying the organic solution over sodium sulfate(anhydrous), the solution is filtered and evaporated to dryness to give300 mg of 2-chlorosulfonyl-4-trifluoromethylpyridine which is useddirectly without further purification, and stored at -78° C. until readyfor use.

PREPARATION 129

2-Chlorosulfonyl-5-trifluoromethylpyridine

Substituting 2-mercapto-5-trifluoromethylpyridine for2-mercapto-4-trifluoromethylpyridine in the reaction above inPreparation 128 gives 2-chlorosulfonyl-5-trifluoromethylpyridine as acolorless oil which slowly crystallizes. This material is used withoutfurther purification and stored at -78° C. until ready for use.

PREPARATION 130

3- 1-5,6-Dihydro-4-hydroxy-2-oxo-6,6-di-n-propyl-2H-pyran-3-yl!-propyl!phenyl-carbamicacid, (Formula SSS-1; R₁ is ethyl; Refer to Chart SSS)

To 7.2 g of AlCl₃ at -70° C., under N₂, is added 180 ml of THF. Themixture is allowed to stir at 0° C. for 15 minutes and 5.38 g of FormulaSSS-A; Refer to Chart SSS, prepared by procedures analogous to thosedescribed in Preparation 17, is added. The reaction mixture is stirredfor 15 minutes and 6.88 g of 3-aminoCbZ-benzaldehyde (Formula SSS-B;Refer to Chart SSS) is added. The reaction mixture is stirred for 15minutes at 0° C. followed by 3 hours at room temperature. The reactionis cooled to 0° C. and 35 g of sodium carbonate monohydrate is added,with vigorous stirring, followed by 1.6 ml of water. After stirring at0° C. for an additional 15 minutes, 120 ml of THF is added and themixture filtered through celite. The celite is washed well with THF andthe THF solution is evaporated to dryness under vacuum to an amber foam.The residue is dissolved in 180 ml of THF, the solution is cooled to -5°C. and 3.2 g of CuBr.Me₂ S added. The mixture is stirred for 15 minutesand 65 ml of a 2M ethylmagnesium chloride in THF solution is added,dropwise, with temperatures not rising above 0° C. The reaction isallowed to stir for an additional 15 minutes and 9 ml of water is slowlyadded followed by 45 ml of 1N HCl. These additions are done at 0° C. Thereaction mixture is poured into 2 L of ethyl ether and 200 ml of wateris added. The aqueous layer is separated and the organic layer isextracted three times with 10% aqueous ammonium carbonate followed byonce with water. The organic solution is dried over anhydrous sodiumsulfate, filtered and evaporated to dryness to give 10.2 g of a crudeamorphous foam. This crude material is chromatographed over silica gelusing 2% ethyl acetate in methelene chloride as eluent to give 4.74 g of3- 1-5,6-dihydro-4-hydroxy-2-oxo-6,6-di-n-propyl-2H-pyran-3-yl!-propyl!phenyl-carbamicacid.

PREPARATION 130A

3- 1-5,6-dihydro-4-hydroxy-2-oxo-6-phenethyl-6-propyl)-2H-pyran-3-yl!-propyl!-phenyl-carbamicacid (Formula RRR-1; R₁ is ethyl; Refer to Chart RRR)

Following the procedure of Preparation 130 beginning with the compoundfrom Preparation 17 the title compound is prepared.

Physical characteristics are as follows:

¹ H NMR (CD₃ OD): δ6.9-7.5, 5.1, 4.0, 1.4-2.7, 0.9.

TLC (silica gel GF): Rf=0.28, 30% ethyl acetate in hexane.

PREPARATION 131

Preparative chiral resolution of 3- 1-5,6-dihydro-4-hydroxy-2-oxo-6,6-di-n-propyl-2H-pyran-3-yl!-propyl!phenyl-carbamicacid (Formula SSS-1; R₁ is ethyl; Refer to Chart SSS) to give twoisomers of 3(R or S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6,6-di-n-propyl-2H-pyran-3-yl!-propyl!phenyl-carbamicacid (Formulas SSS-3 and SSS-4; R₁ is ethyl; Refer to Chart SSS).

Samples of the title compound of Preparation 130 are injected onto a2.1×25 cm Chiralcel OD column and eluted with 20% isopropanol (V/V) inhexane at 10 mL/min. The material eluting near 19.1 minutes is 3(R orS)- 1-5,6-dihydro-4-hydroxy-2-oxo-6,6-di-n-propyl-2H-pyran-3-yl!-propyl!phenyl-carbamicacid, (α)25D +26° (methanol), (Formula SSS-3; Refer to Chart SSS)(peak 1) and that eluting near 37.7 minutes is 3(R or S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6,6-di-n-propyl-2H-pyran-3-yl!-propyl!phenyl-carbamicacid ((α)²⁵ _(D) -27° (methanol), (Formula SSS-4; Refer to Chart SSS)(peak 2). The pools are concentrated separately on a rotary evaporator(ca. 30 mm, bath at 50° maximum) to give white amorphous solids.

PREPARATION 132

3(R or S)-1-(3-aminophenyl)-propyl!-4-hydroxy-5,6-dihydro-6,6-dipropyl-2H-pyran-2-one(Formula SSS-5; R₁ is ethyl; Refer to Chart SSS)

To 1.04 g of 3(R or S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6,6-di-n-propyl-2H-pyran-3-yl!-propyl!phenyl-carbamicacid (Formula SSS-3; Refer to Chart SSS) of Preparation 131, thecompound identified as peak 1 from the chiral resolution of the productof Preparation 131, is added 20 ml of methanol and 1.29 g of ammoniumformate. When dissolution is complete, 275 mg of 10% Pd/C is added andthe reaction mixture is stirred at room temperature for 60 minutes. Thereaction mixture is filtered (celite) and the methanolic solution isevaporated to dryness to give a crude solid. The crude solid ispartitioned between methylene chloride and water. The organic layer iswashed twice with water and dried over anhydrous sodium sulfate. Themethylene chloride solution is filtered and evaporated to dryness togive 625 mg of 3(R or S)-1-(3-aminophenyl)-propyl!-4-hydroxy-5,6-dihydro-6,6-dipropyl-2H-pyran-2-oneas an amorphous foam.

Physical characteristics are as follows:

MS(EI): 331

(α)²⁵ _(D) +38° (c=0.3715, methanol).

PREPARATION 133

3(R or S)-1-(3-aminophenyl)-propyl!-4-hydroxy-5,6-dihydro-6,6-di-n-propyl-2H-pyran-2-one(Formula SSS-6; R₁ is ethyl; Refer to Chart SSS)

To 825 mg of 3(R or S)-1-(3-aminophenyl)-propyl!-4-hydroxy-5,6-dihydro-6,6-dipropyl-2H-pyran-2-one(Formula SSS-4; Refer to Chart SSS), of Preparation 131, the compoundidentified as peak 2 from the chiral resolution of the product ofPreparation 131, is added 20 ml of methanol and 1.02 g of ammoniumformate. When dissolution is complete, 210 mg of 10% Pd/C is added andthe reaction mixture is stirred at room temperature for 60 minutes. Thereaction mixture is filtered (celite) and the methanolic solution isevaporated to dryness. The crude solid is partitioned between methylenechloride and water. The organic layer is washed twice with water anddried over anhydrous sodium sulfate. The methylene chloride solution isfiltered and evaporated to dryness to give 483 mg of title compound asan amorphous foam.

Physical characteristics are as follows:

MS(EI): 331

(α)²⁵ _(D) -39° (c=0.2680, methanol).

EXAMPLE 280

5-Trifluoromethyl-N- 3- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide(Formula SSS-9; R₁ is ethyl; R₂ is 5-trifluoromethylpyridine; Refer toChart SSS)

The title compound of Preparation 130 is deprotected as in Preparation132 to give the compound of formula SSS-2. To 132 mg of formula SSS-2 isadded 15 ml of methylene chloride and 66 microliters of pyridine. Thereaction solution is cooled to -5° C. and 98 mg of2-chlorosulfonyl-5-trifluoromethylpyridine (product of Preparation 129)is added. After stirring at 0° C. for 60 minutes the solution is placedon a silica gel column and eluted with 10% ethyl acetate in methylenechloride until the 5-trifluoromethyl-N- 3- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamideis collected. Rf=0.6 in 10% ethyl acetate in methylene chloride.Evaporation of the organic solution to dryness gives 177 mg of5-trifluoromethyl-N- 3- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide

Physical characteristics are as follows:

MS(EI): 540, 497, 411, 401, 383, 342, 331, 197, 174, 146, 133.

HRMS: 540.1938

Rf=0.6 in 10% ethyl acetate in methylene chloride.

¹ H NMR(MeOD): δ8.91, 8.21-8.19, 7.12, 6.98-6.96, 6.86-6.83, 3.85-3.79,2.46, 2.10-1.98, 1.84-1.75, 1.58-1.47, 1.27-1.15, 0.82-0.72 ppm

EXAMPLE 281

5-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide(Formula SSS-7; R₁ is ethyl; R₂ is 5-trifluoromethylpyridine; Refer toChart SSS)

To 66 mg of the title product from Preparation 132 (Formula SSS-5; ChartSSS) is added 8 ml of methylene chloride and 33 microliters of pyridine.The reaction solution is cooled to -5° C. and 49 mg of2-chlorosulfonyl-5-trifluoromethylpyridine (product of Preparation 129)is added. After stirring at 0° C. for 60 minutes the solution is placedon a silica gel column and eluted with 10% ethyl acetate in methylenechloride until the 5-trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamideis collected. Rf=0.6 in 10% ethyl acetate in methylene chloride.Evaporation of the organic solution to dryness gives 69 mg of the titlecompound.

Physical characteristics are as follows:

MS(EI): 540, 497, 411, 401, 383, 342, 331, 197, 174, 146, 133.

Rf=0.6 in 10% ethyl acetate in methylene chloride

¹ H NMR(MeOD): δ8.91, 8.21-8.19, 7.12, 6.98-6.96, 6.86-6.83, 3.85-3.79,2.46, 2.10-1.98, 1.84-1.75, 1.58-1.47, 1.27-1.15, 0.82-0.72 ppm

EXAMPLE 282

5-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide(Formula SSS-8; R₁ is ethyl; R₂ is 5-trifluoromethylpyridine; Refer toChart SSS)

Following the procedure of Example 281 but substituting the product ofPreparation 133 (formula SSS-6) gives 5-trifluoromethyl-N- 3-(R or S)-1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamideas an amorphous foam.

Physical characteristics are as follows:

MS(EI): 540, 497, 411, 401, 383, 342, 331, 197, 174, 146, 133.

Rf=0.6 in 10% ethyl acetate in methylene chloride

¹ H NMR(MeOD): δ8.91, 8.21-8.19, 7.12, 6.98-6.96, 6.86-6.83, 3.85-3.79,2.46, 2.10-1.98, 1.84-1.75, 1.58-1.47, 1.27-1.15, 0.82-0.72 ppm

EXAMPLE 283

4-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide(Formula SSS-7; R₁ is ethyl; R₂ is 4-trifluoromethylpyridine; Refer toChart SSS)

Following the procedure of Example 281 but substituting the product ofPreparation 128 for the pyridylsulfonylchloride gives4-trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl-propyl!-phenyl!-2-pyridinesulfonamideas an amorphous foam.

Physical characteristics are as follows:

MS(EI): 146, 145, 139, 133, 71, 57, 55, 43, 41

HRMS: 540.1902

EXAMPLE 284

4-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide(Formula SSS-8; R₁ is ethyl; R₂ is 4-trifluoromethylpyridine; Refer toChart SSS)

Following the procedure of Example 282 but substituting the product ofPreparation 128 for the pyridylsulfonylchloride gives4-trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamideas an amorphous foam.

Physical characteristics are as follows:

MS(EI): 146, 145, 139, 133, 71, 57, 55, 43, 41

HRMS: 540.1896

EXAMPLE 285

5-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide(Formula TTT-6; R₁ is t-butyl; R₂ is n-propyl; R₃ is5-trifluoromethyl-2-pyridinyl; Refer to Chart TTT)

Following the procedure of Example 281 but using Isomer 1 of Preparation144 (Formula TTT-4; Chart TTT; R₁ is t-butyl, R₂ is n-propyl) gives5-trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamideas an amorphous solid.

Physical characteristics are as follows:

MS(EI): 163, 162, 147, 146, 69, 57, 56, 43, 41

HRMS: 568.2213

EXAMPLE 286

5-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!1-2-pyridinesulfonamide(Formula TTT-7; R₁ is t-butyl; R₂ is n-propyl; R₃ is5-trifluoromethylpyridine; Refer to Chart TTT)

Following the procedure of Example 281 but substituting Isomer 2 ofPreparation 144 (Formula TTT-5; Chart TTT; R₁ is t-butyl; R₂ isn-propyl) gives 5-trifluoromethyl-N- 3- 1(R orS)-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamideas an amorphous solid.

Physical characteristics are as follows:

HRMS: 568.2237

EXAMPLE 287

5-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide(Formula TTT-6; R₁ is ethyl; R₂ is phenyl; R₃ is5-trifluoromethylpyridine; Refer to Chart TTT)

Following the procedure of Example 281 but using Isomer 1 of Preparation145 (Formula TTT-4; Chart TTT; R₁ is ethyl; R₂ is phenyl) gives5-trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamideas an amorphous solid.

Physical characteristics are as follows:

MS(EI): 665, 647, 456, 455, 333, 134, 133, 117, 105, 91

EXAMPLE 288

5-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide(Formula TTT-7; R₁ is ethyl; R₂ is phenyl; R₃ is5-trifluoromethylpyridine; Refer to Chart TTT)

Following the procedure of Example 281 but substituting Isomer 2 ofPreparation 145 (Formula TTT-5; Chart TTT; R₁ is ethyl; R₂ is phenyl)gives 5-trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamideas an amorphous solid.

Physical characteristics are as follows:

HRMS: 665.2300

MS(EI): 665, 647, 456, 455, 333, 134, 133, 117, 105, 91

EXAMPLE 289

4-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide(Formula TTT-6; R₁ is ethyl; R₂ is phenyl; R₃ is4-trifluoromethylpyridine; Refer to Chart TTT)

Following the procedure of Example 281 but substituting Isomer 1 ofPreparation 145 (Formula TTT-4; Chart TTT; R₁ is ethyl; R₂ is phenyl)gives 5-trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamideas an amorphous solid.

Physical characteristics are as follows:

MS(EI): 666, 665, 647, 134, 133, 117, 105, 91

HRMS: 665.2306

EXAMPLE 290

4-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-diphenethyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide(Formula TTT-7; R₁ is ethyl; R₂ is phenyl; R₃ is4-trifluoromethylpyridine; Refer to Chart TTT)

Following the procedure of Example 281 but substituting Isomer 2 ofPreparation 145 (Formula TTT-5; Chart TTT; R₁ is ethyl; R₂ is phenyl)gives 4-trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamideas an amorphous solid.

Physical characteristics are as follows:

HRMS: 665.2306

MS(EI): 666, 665, 647, 134, 133, 117, 105, 91

EXAMPLE 291

4-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide(Formula TTT-6; R₁ is t-butyl; R₂ is methyl; R₃ is4-trifluoromethylpyridine; Refer to Chart TTT)

Following the procedure of Example 283 but substituting Isomer 1 ofPreparation 144 (Formula TTT-4; Chart TTT; R₁ is t-butyl; R₂ is methyl)gives 4-trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamideas an amorphous solid.

Physical characteristics are as follows:

MS(EI): 525, 512, 428, 411, 302, 284, 258, 146, 57

HRMS: 568.2209

EXAMPLE 292

4-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide(Formula TTT-7; R₁ is t-butyl; R₂ is methyl; R₃ is4-trifluoromethylpyridine; Refer to Chart TTT)

Following the procedure of Example 283 but substituting Isomer 2 ofPreparation 144 (Formula TTT-5; Chart TTT; R₁ is t-butyl; R₂ is methyl)gives 4-trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamideas an amorphous solid.

Physical characteristics are as follows:

MS(EI): 569, 551, 511, 493, 439, 371, 360, 303, 284, 161, 139

HRMS (MI+H⁺): 569.2297

PREPARATION 134

N- 3- 1-5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!phenylcarbamicacid, phenylmethyl ester (Formula RRR-1; R₁ is t-butyl; Refer to ChartRRR)

To 4.8 g of AlCl₃ at -70° C., under N₂, is added 120 ml of THF. Themixture is allowed to stir at 0° C. for 15 minutes and 4.68 g of(formula RRR-A) of Preparation 17 is added. The reaction mixture isstirred for 15 minutes and 4.59 g of 3-aminoCbZ-benzaldehyde (formulaRRR-B) is added. The reaction mixture is stirred for 15 minutes at 0° C.followed by 3 hours at room temperature. The reaction is cooled to 0° C.and 26 g of sodium carbonate monohydrate (0.21M) is added, with vigorousstirring, followed by 1.08 ml of water. After stirring at 0° C. for anadditional 15 minutes, the mixture is treated with 120 ml of THF andfiltered through celite. The celite is washed well with THF and the THFsolution is evaporated to dryness under vacuum to an amber foam. Theresidue is dissolved in 120 ml of THF, the solution is cooled to -5° C.and 2.1 g of CuBr.Me₂ S added. The mixture is stirred for 15 minutes and65 mL of a 1M t-butylmagnesium chloride in THF solution is added,dropwise, with temperatures not rising above 0° C. The reaction isallowed to stir for an additional 15 minutes at 0° C. and 6 ml of wateris slowly added followed by 30 ml of 1N HCl. The reaction mixture ispoured into 1.3 L of ethyl ether. The aqueous layer is separated and theorganic layer is extracted three times with 10% aqueous ammoniumcarbonate followed by once with water. The organic solution is driedover anhydrous sodium sulfate, filtered and evaporated to dryness togive an amorphous foam. This crude material is chromatographed oversilica gel using 30% ethyl acetate in hexane as eluent to give 6.15 gthe title product.

PREPARATION 135

Preparative resolution of N- 3- 1-5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl-carbamicacid, phenylmethyl ester (Formula RRR-1; R₁ is t-butyl) into fourisomers, 3-(R or S)- 1- 5,6-Dihydro-4-hydroxy-2-oxo-6-(R orS)-(2-phenethyl)-6-(R orS)-n-propyl-2H-pyran-3-yl!-2,2-dimethyl-propyl!phenyl-carbamic acid,phenylmethyl ester (Formulas RRR-3 to 6; R₁ is t-butyl; Refer to ChartRRR)

The four constituent enantiomers are (in order of elution from system A)Isosmer 1 (Formula RRR-4; refer to Chart RRR), Isomer 2 (Formula RRR-3;refer to Chart RRR), Isomer 3 (Formula RRR-5; refer to Chart RRR), andIsomer 4 (Formula RRR-6; refer to Chart RRR). System A consists of a0.46×25 cm Chiralcel OD-H column eluted at 0.5 mL/min with 20%isopropanol and 0.1% trifluoracetic acid in hexane (V/V). (ChiralcelOD-H is a registered trademark of Chiral Technologies, Inc., Exton Pa.19341.)

The first phase of the resolution is accomplished with a 2.1×25 cm(R,R)Whelk-O 1 column eluted with 20% (V/V) isopropanol in hexane at 12mL/min. ((R,R)Whelk-O 1 is a registered trademark of Regis Technologies,Inc., Morton Grove, Ill. 60053.) The peaks eluting at approximately 35and 41 min are, respectively, a mixture of Isomer 3 and Isomer 4 and amixture of Isomers 1 and 2 and as judged from System A, above. The twomixtures are further treated as below.

In the second phase of the resolution, the mixture from above thatelutes near 41 minutes is injected onto a 2.1×25 cm Chiralcel OD column(Chiral Technologies, Inc.) and elutes with 15% isopropanol and 0.05%trifluoracetic acid in hexane (V/V) at 9.0 mL/min. The peaks that elutenear 11.0 and 22.0 minutes are designated respectively, peaks 1 and 2and as judged from System A.

In the final phase of the resolution, the mixture that elutes from theWhelk-O column near 35 minutes is injected onto a 2.2×25 cm Chiralcel ODcolumn and elutes with 35% isopropanol and 0.1% trifluoroacetic acid(V/V) in hexane at 9.0 mL/min. The isomer that elutes near 9.7 minutesis designated peak 3 and the one that elutes near 16.6 minutes isdesignated peak 4.

PREPARATION 136

3-1-(3-Aminophenyl)-2,2-dimethyl-propyl!-5,6-dihydro-4-hydroxy-6-phenethyl-6-n-propyl-pyran-2-one(Formula RRR-2, Refer to Chart RRR)

To 590 mg of 3- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl-carbamicacid of Preparation 134, is added 10 ml of methanol and 660 mg ofammonium formate. When all the reactants are dissolved, 140 mg of 10%Pd/C is added and the reaction is allowed to stir at room temperaturefor 60 minutes. The reaction is filtered (celite) and the filter pad iswashed well with methanol and the methanol solution is evaporated undervacuum to a crude solid. The solid is partitioned between water andmethylene chloride, and the methylene chloride layer is washed twicewith water, dried over anhydrous sodium sulfate and evaporated todryness to give 372 mg of 3-1-(3-amino-pheny)-2,2-dimethyl-propyl!-5,6-dihydro-4-hydroxy-6-phenethyl-6-n-propyl-pyran-2-one.This material is identical to material described earlier (Formula T-4;refer to Chart T).

PREPARATION 137

3(R or S)-1-(3-amino-phenyl)-2,2-dimethyl-propyl!-5,6-dihydro-4-hydroxy-6(R orS)-phenethyl-6(R or S)-propyl-pyran-2-one (Formula RRR-7; R₁ is t-butyl;Refer to Chart RRR)

Following the procedure of Preparation 136 but substituting the compoundin Preparation 135 designated peak 2 for the compound of Preparation 134gives 3(R or S)-1-(3-amino-pheny)-2,2-dimethyl-propyl!-5,6-dihydro-4-hydroxy-6(R orS)-phenethyl-6(R or S)-propyl-pyran-2-one as an amorphous foam.

Physical characteristics are as follows:

MS(EI): 421, 365, 164, 163, 147, 146, 118, 107, 91, 57.

HRMS: 421.2617

PREPARATION 138

3(R or S)-1-(3-Amino-pheny)-2,2-dimethyl-propyl!-5,6-dihydro-4-hydroxy-6(R orS)-phenethyl-6(R or S)-propyl-pyran-2-one (Formula RRR-8; R₁ is t-butyl;Refer to Chart RRR)

Following the procedure of Preparation 136 but substituting the compoundof Preparation 135 designated peak 1 for the compound of Preparation 134gives 3(R or S)-1-(3-amino-pheny)-2,2-dimethyl-propyl!-5,6-dihydro-4-hydroxy-6(R orS)-phenethyl-6(R or S)-propyl-pyran-2-one as an amorphous foam.

Physical characteristics are as follows:

MS(EI): 421, 365, 164, 163, 147, 146, 118, 107, 91, 57.

EXAMPLE 293

5-Trifluoromethyl-N- 3- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide(Formula RRR-15; R₁ is t-butyl; R₂ is 5-trifluoromethyl; Refer to ChartRRR).

Following the procedure of Example 281 but substituting the product ofPreparation 136 for the product of Preparation 132 gives5-trifluoromethyl-N- 3- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamideas an amorphous foam.

Physical characteristics are as follows:

MS(EI): 497, 411, 401, 383, 343, 331, 197, 174, 146, 133

HRMS: 540.1938

EXAMPLE 294

5-Trifluoromethyl-N- 3(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide(Formula RRR-11; R₁ is t-butyl; R₂ is 5-trifluoromethyl; Refer to ChartRRR)

Following the procedure of Example 281 but substituting the product ofPreparation 137 for the product of Preparation 132 gives5-trifluoromethyl-N- 3 (R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamideas an amorphous foam.

Physical characteristics are as follows:

MS(EI): 373, 355, 201, 146, 145, 118, 117, 91, 57.

HRMS:630.2394

EXAMPLE 295

5-Trifluoromethyl-N- 3 (R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide(Formula RRR-12; R₁ is t-butyl; R₂ is 5-trifluoromethyl; Refer to ChartRRR)

Following the procedure of Preparation 281 but substituting the productof Preparation 138 for the product of Preparation 132 gives5-trifluoromethyl-N- 3(R or S)-(-(1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamideas an amorphous foam.

Physical characteristics are as follows:

MS(EI): 373, 355, 201, 146, 145, 118, 117, 91, 57.

HRMS:630.2379

EXAMPLE 296

4-Trifluoromethyl-N- 3(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide(Formula RRR-11, R₁ is t-butyl; R₂ is 4-trifluoromethyl; Refer to ChartRRR)

Following the procedure of Example 294 but substituting the product ofPreparation 128 for the product of Preparation 129 gives4-trifluoromethyl-N- 3(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamideas an amorphous foam.

Physical characteristics are as follows:

MS(EI): 633, 632, 631, 614, 613, 346, 201, 146, 91, 57

HRMS: 631.2444

EXAMPLE 297

4-Trifluoromethyl-N- 3(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide(Formula RRR-12; R₁ is t-butyl; R₂ is 4-trifluoromethyl; Refer to ChartRRR)

Following the procedure of Example 295 but substituting the product ofPreparation 128 for the product of Preparation 129 gives4-trifluoromethyl-N- 3(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamideas an amorphous foam.

Physical characteristics are as follows:

MS(EI): 633, 632, 631, 614, 613, 346, 201, 146, 91, 57.

HRMS: 631.2450

EXAMPLE 298

5-Trifluoromethyl-N- 3(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide(Formula RRR-11; R₁ is ethyl; R₂ is 5-trifluoromethyl; Refer to ChartRRR)

Following the procedure of Example 294 but substituting the product ofPreparation 147A gives 5-trifluoromethyl-N- 3(R or S)-(-(1-5,6-dihydro-4-hydroxy-2-oxo-6(R or S)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-propyl)phenyl!-2-pyridinesulfonamide as anamorphous foam.

Physical characteristics are as follows:

MS(EI): 605, 604, 603, 602, 586, 585, 393, 201, 133, 91

HRMS: 603.2153

EXAMPLE 298A

5-Trifluoromethyl-N- 3(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide(Formula RRR-12; R₁ is ethyl; R₂ is 5-trifluoromethyl; Refer to ChartRRR)

Following the procedure of Example 294 but substituting the aminederived from Isomer 1 of Preparation 147 (derived following theprocedure of Preparation 147A) gives the title compound as an amorphousfoam.

Physical characteristics are as follows:

¹ H NMR (CD₃ OD): δ8.9, 8.2, 8.0, 7.0-7.3, 3.9, 2.4-2.7, 1.2-2.2,0.8-1.0.

TLC (silica gel GF): Rf=0.19, 40% ethyl acetate in hexane.

PREPARATION 139

(5-Nitro-pyridin-2-yl)-isothiourea hydrochloride (Formula UUU-2) Referto Chart UUU

A solution of 3.81 g of thiourea in 75 mL of hot absolute ethanol istreated with 7.61 g of 2-chloro-5-nitropyridine (Formula UUU-1) and isheated at reflux for 6 hours. The mixture is then cooled to 0° C. andthe precipitated solid is collected. The solid is washed sequentiallywith cold absolute ethanol and chloroform. The solid is dried in vacuoto afford 6.91 g of the title product as a light brown solid.

Physical characteristics are as follows:

MP 175° C. (dec.)

¹ H NMR (CD₃ OD) δ7.9, 8.6, 9.4 ppm

PREPARATION 140

5-Nitro-2-thiopyridine (Formula UUU-3) Refer to Chart UUU

A solution of 1.65 g of sodium carbonate in 50 mL of water is treatedwith 2.35 g of the title compound of Preparation 139. The mixture ischarged with a solution of 2.75 g of sodium hydroxide in 50 mL of waterand the resulting mixture is warmed to room temperature. After stirringfor 1 hour, the mixture is heated to 95° C. for 1 hour and finallycooled to room temperature. The aqueous mixture is extracted with twoportions of diethyl ether and then carefully acidified with 6N aqueoushydrochloric acid. The orange precipitated solid is collected and washedsequentially with cold dilute aqueous hydrochloric acid and water. Thesolid is dried in vacuo to afford 1.27 g of the title product as anorange solid.

Physical characteristics are as follows:

MP 167°-170° C.

¹ H NMR (CDCl₃ --CD₃ OD) δ7.4, 7.9, 8.5 ppm

PREPARATION 141

5-Nitro-2-pyridinesulfonyl chloride (Formula UUU-4) Refer to Chart UUU

To a suspension of 1.27 g of the title compound of Preparation 140 in 25mL of 1N aqueous hydrochloric acid and 5 mL of acetic acid at 0° C. isvigorously bubbled in chlorine gas. After 15 minutes, the chlorine gasaddition is ceased and replaced with nitrogen gas. The resulting solidis collected and washed sequentially with cold dilute aqueoushydrochloric acid and water. The solid is dried in vacuo to afford 1.60g of the title product as a tan solid.

Physical characteristics are as follows:

MP 77°-80° C.

¹ H NMR (CDCl₃) δ8.3, 8.8, 9.6 ppm

PREPARATION 142

N- 3-(1-5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-5-nitro-2-pyridinesulfonamide(Formula UUU-5: R₁ is 2-phenylethyl, R₂ is propyl, R₃ is tert-butyl)Refer to Chart UUU

To a solution of 210 mg of the title compound of Preparation 81 (FormulaT-4) in 2 mL of dichloromethane at 0° C. is added 80 μL of pyridinefollowed by 111 mg of the title compound of Preparation 141 (FormulaUUU-4). After warming to room temperature overnight, the reactionmixture is column chromatographed on flash silica gel eluting with 3% to9% ethyl acetate in dichloromethane to provide 303 mg of the titlecompound as a yellow foam.

Physical characteristics are as follows:

¹ H NMR (CDCl₃ --CD₃ OD) δ0.8-1.0, 1.2-1.4, 1.6-1.9, 2.4-2.7, 4.0,6.9-7.4, 8.0, 8.5, 9.4 ppm

HRMS 608.2412 (EI)

EXAMPLE 299

5-Amino-N- 3-(1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide(Formula UUU-6: R₁ is 2-phenylethyl, R₂ is propyl, R₃ is tert-butyl)Refer to Chart UUU

To a solution of 300 mg of the title compound of Preparation 142(Formula UUU-5) in 5 mL of methanol under argon is added 500 mg ofammonium formate followed by 100 mg of 10% palladium on carbon. After 1hour, the reaction mixture is filtered through a pad of Celite withmethanol washes. The combined filtrates are concentrated under reducedpressure and the residue is repeatedly triturated with portions ofdichloromethane. The combined dichloromethane washes are concentratedunder reduced pressure and the residue is column chromatographed onflash silica gel eluting with 50% ethyl acetate in dichloromethane toprovide 246 mg of the title compound as a white solid.

Physical characteristics are as follows:

¹ H NMR (CDCl₃ --CD₃ OD) δ0.8-1.0, 1.2-1.4, 1.5-2.0, 2.4-2.6, 4.0, 6.7,6.8-7.3, 7.4, 7.9 ppm

HRMS 577.2617 (EI)

EXAMPLE 300-327

Following the procedures and preparations described above and usingstarting materials known and available to one of ordinary skill inorganic synthesis, the following additional compounds in Table 3 of thepresent invention are made from the compounds prepared in the followingpreparations:

PREPARATION 143

Preparative separation of N- 3- 1-5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl-carbamicacid phenylmethyl ester, to give 4 isomers

The title compound of Preparation 134 is separated into four constituentsteroisomers which are (in order of elution from system A) 4 isomers:Isomer 1, Isomer 2, Isomer 3, and Isomer 4 with the followingapproximate observed retention times 10.5, 14.9, 21.4 and 65.2 minutesrespectively. System A consists of a 0.46×25 cm Chiralcel OD-H columneluting at 0.5 mL/min with 20% isopropanol and 0.1% trifluoracetic acidin hexane (V/V). (Chiralcel OD-H is a registered trademark of ChiralTechnologies, Inc., Exton Pa. 19341.)

The first phase of the separation is accomplished with a 2.1×25 cm(R,R)Whelk-O 1 column eluting with 20% (V/V) isopropanol in hexane at 12mL/min. ((R,R)Whelk-O 1 is a registered trademark of Regis Technologies,Inc., Morton Grove, Ill. 60053.) The peaks eluting at approximately 35and 41 min are, respectively, a mixture of Isomers 3 and 4 and a mixtureof Isomers 1 and 2 as judged from System A, above. The two mixtures arefurther treated as below.

In the second phase of the separation, the mixture from above thatelutes near 41 minutes is injected onto a 2.1×25 cm Chiralcel OD column(Chiral Technologies, Inc.) and eluting with 15% isopropanol and 0.05%trifluoracetic acid in hexane (V/V) at 9.0 mL/min. The peaks that elutenear 11.0 and 22.0 minutes are, respectively, Isomer 1 and Isomer 2 asjudged from System A.

In the final phase of the separation, the mixture that elutes from the(R,R)Whelk-O 1 column near 35 minutes is injected onto a 2.2×25 cmChiralcel OD column eluting with 35% isopropanol and 0.1%trifluoroacetic acid (V/V) in hexane at 9.0 mL/min. The isomer thatelutes near 9.7 minutes is Isomer 3 and the one that elutes near 16.6minutes is Isomer 4.

In both phases of the separation of stereoisomers, fractions are pooledafter assay with System A and pools are concentrated to dryness on arotary evaporator.

PREPARATION 144

Resolution of N- 3-(1-5,6-Dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethylpropyl)-phenyl!carbamicacid, phenylmethyl ester to give 2 isomers

Samples of the starting compound (up to 1.0 gm each run) are injectedonto a 5.1×50 cm Chiralcel OD column (Chiral Technologies, Inc.). Theenantiomers elute at about 23 min (This corresponds to thebenzyloxycarbonyl protected analogue of amine (Isomer 1) (EI-MS: 359M+!; ¹ H NMR (CDCl₃ --CD₃ OD): 7.1-6.9, 6.5, 4.2, 2.6-2.3, 1.8-1.2, 1.1,0.9; TLC: R_(f) =0.42 (10% ethyl acetate in dichloromethane)), and atabout 33 min (This corresponds to the benzyloxycarbonyl protectedanalogue of amine (Isomer 2) (EI-MS: 359 M+!; ¹ H NMR (CDCl₃ --CD₃ OD):7.1-6.9, 6.5, 4.2, 2.6-2.3, 1.8-1.2, 1.1, 0.9; TLC: R_(f) =0.42 (10%ethyl acetate in dichloromethane)). The mobile phase is 20% isopropanoland 0.1% acetic acid in hexane (V/V) pumped at 60 mL/min. The purity ischecked on a 0.46×25 cm Chiralcel OD-H column (Chiral Technologies,Inc.). The mobile phase is 20% isopropanol in hexane (V/V) and 0.05%trifluoroacetic acid pumped at 0.5 mL/min. The observed retention timesare 8.9 and 16.7 min (monitor set at 238 nm) for Isomer 1 and Isomer 2,respectively.

PREPARATION 145

Resolution of N- 3-(1-6,6-Bis(2-phenylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!propyl)phenyl!carbamicacid, phenylmethyl ester to give 2 isomers

Samples of the starting compound (up to 1.3 gm each run) are injectedonto a 5.1×50 cm Chiralcel OD column (Chiral Technologies, Inc.). Theenantiomers are eluted with 20% isopropanol and 0.025% acetic acid inhexane (V/V) at 60 mL/min until the first enantiomer elutes. At thispoint (approximately 120 min into the run) the flow rate is increased to90 mL/min to expedite elution of the second enantiomer. The enantiomerselute near 91.2 min (This is the corresponding benzyloxycarbonylanalogue of amine Isomer 1 and near 132 min (This is the correspondingbenzyloxycarbonyl analogue of amine Isomer 2. The purity is checked on a0.46×25 cm Chiralcel OD-H column. The mobile phase is 30% isopropanol inhexane (V/V) pumped at 0.5 mL/min.

PREPARATION 146

5-Carbamoylpyridine-2-sulfonyl chloride (Formula VVV-2) Refer to ChartVVV

Into a cold (0°), stirred suspension of 400 mg of2-mercapto-5-carbamoylpyridine of formula VVV-1 in 7.5 ml of 1N HCl ispassed a brisk stream of chlorine gas. After ten minutes, the suspensionis filtered, and the solid washed well with water and dried in vacuo.Obtained is 517 mg of the title compound as a nearly white solid.

EXAMPLE 328

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6-(2-(4-fluorophenyl)ethyl-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-4-cyanobenzenesulfonamide(Formula U-8: R₁ is tert-butyl, R₂ is 4-cyanophenyl) Refer to Chart U

Using the general sulfonation procedure of Example 252, 88 mg of theamine of Preparation 86 (Formula U-7, R₁ is tert-butyl) is reacted with4-cyanobenzenesulfonyl chloride. Flash chromatography on silica gelusing 10% ethyl acetate in dichloromethane provides 117 mg of the titlecompound as an amorphous white solid.

Physical characteristics are as follows:

¹ H NMR δ0.90, 1.3, 1.7, 2.5, 3.6, 6.8-7.4, 7.6, 7.8 ppm

HRMS: 605.2478

R_(f) 0.36 (10% ethyl acetate in dichloromethane)

EXAMPLE 329

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6-(2-(4-fluorophenyl)ethyl-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-8-quinolinesulfonamide(Formula U-8: R₁ is tert-butyl, R₂ is 8-quinolyl) Refer to Chart U

Using the general sulfonylation procedure of Example 252, 88 mg of theamine of Preparation 86 (Formula U-7, R₁ is tert-butyl) is reacted with8-quinolinesulfonyl chloride. Flash chromatography on silica gel using5-10% ethyl acetate in dichloromethane provides 101 mg of the titlecompound as an amorphous white solid.

Physical characteristics are as follows:

¹ H NMR δ0.63, 0.9, 1.1, 1.3, 1.6-1.9, 2.4-2.6, 6.7-7.6, 8.0, 8.2, 9.1ppm

HRMS: 631.2638

R_(f) 0.30 (5% ethyl acetate in dichloromethane)

EXAMPLE 330

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is phenethyl, R₃ is ethyl, R₄ is1-methylimidazole-4-yl) Refer to Chart D

Using the general sulfonylation procedure of Example 252, 77 mg of theamine of Formula D-5, wherein R₁ and R₂ are phenethyl and R₃ is ethyl,is reacted with 1-methylimidazole-4-sulfonyl chloride. Flashchromatography on silica gel using 3% methanol in dichloromethaneprovides 97.0 mg of the title compound as a crystalline white solid.

Physical characteristics are as follows:

¹ H NMR δ0.88, 1.9-2.2, 2.6, 3.6-3.8, 3.97, 6.9-7.5 ppm

HRMS: 600.2521

R_(f) 0.31 (5% methanol in dichloromethane)

EXAMPLE 331

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula D-6: R₁ is phenethyl, R₂ is phenethyl, R₃ is ethyl, R₄ is5-cyanopyridine-2-yl) Refer to Chart D

Using the general sulfonylation procedure of Example 252, 77 mg of theamine of Formula D-5, wherein R₁ and R₂ phenethyl and R₃ is ethyl,isreacted with 5-cyanopyridine-2-sulfonyl chloride. Flash chromatographyon silica gel using 10% ethyl acetate in dichloromethane provides 88.3mg of the title compound as a crystalline white solid.

Physical characteristics are as follows:

¹ H NMR δ0.85, 1.8-2.2, 2.5-2.7, 3.97, 6.9-7.4, 7.9, 8.8 ppm.

HRMS: 622.2355

R_(f) 0.28 (10% ethyl acetate in dichloromethane)

EXAMPLE 332

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-carbamoylpyridine-2-sulfonamide(Formula U-8: R₁ is ethyl, R₂ is 5-carbamoylpyridine-2-yl) Refer toChart U

Using the general sulfonylation procedure of Example 252, 82 mg of theamine of Formula U-7, wherein R₁ is ethyl, is reacted with5-carbamoylpyridine-2-sulfonyl chloride of Preparation 146. Flashchromatography on silica gel using 3-6% methanol in dichloromethaneprovides 55.4 mg of the title compound as an amorphous solid.

Physical characteristics are as follows:

¹ H NMR δ0.7-0.9, 1.3, 1.6-2.1, 2.5, 3.9, 6.8-7.3, 7.8, 8.2 ppm.

HRMS: 596.2216

R_(f) 0.16 (5% methanol in dichloromethane)

EXAMPLE 333

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-(4-fluorophenyl)ethyl)-2H-pyran-3-yl)propyl}phenyl!-5-carbamoylpyridine-2-sulfonamide(Formula V-8: R₁ is ethyl, R₂ is 5-carbamoylpyridine-2-yl) Refer toChart V

Using the general sulfonylation procedure of Example 252, 98 mg of theamine of formula V-7, wherein R₁ is ethyl) is reacted with5-carbamoylpyridine-2-sulfonyl chloride of Preparation 146. Flashchromatography on silica using 3-6% methanol in dichloromethane provides58.3 mg of the title compound as an amorphous solid.

Physical characteristics are as follows:

¹ H NMR δ0.83, 1.8-2.2, 2.5-2.6, 6.8-7.2, 7.8, 8.1, 9.0 ppm.

HRMS: 676.2297

R_(f) 0.17 (5% methanol in dichloromethane)

EXAMPLE 334

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl}phenyl!-5-carbamoylpyridine-2-sulfonamide(Formula D-6: R₁ is propyl, R₂ is propyl, R₃ is ethyl, R₄ is5-carbamoylpyridine-2-yl) Refer to Chart D

Using the general sulfonylation procedure of Example 252, 66 mg of theamine of Formula D-5 (R₁ and R₂ are propyl, R₃ is ethyl) is coupled with5-carbamoylpyridine-2-sulfonyl chloride of Preparation 146 to yield,after flash chromatography on silica gel using 3-6% methanol indichloromethane, 83.8 mg of the title compound as an amorphous whitesolid.

Physical characteristics are as follows:

¹ H NMR δ0.7-0.9, 1.2-2.1, 3.87, 7.0-7.3, 7.8, 8.2 ppm.

HRMS: 516.2156

R_(f) 0.22 (5% methanol in dichloromethane)

PREPARATION 147

Resolution of N- 3-1-(4-Hydroxy-5,6-dihydro-2-oxo-6-phenethyl-6-propyl-2H-pyran-3-yl)propyl!phenyl!-carbamicacid, phenylmethyl ester to give 4 isomers (Formula WWW-2: R₁ isphenethyl, R₂ is propyl, R₃ is ethyl) Refer to Chart WWW and RRR

The four isomers of the product of Preparation 130A (Formula RRR-1; R₁=ethyl) are (in order of increasing retention time on System B): (ca.16.9 min) (Isomer 1), (ca. 28.0 min) (Isomer 2), (ca. 38.2 min) (Isomer3) and (ca. 49.8 min) (Isomer 4). System B consists of a 0.46×25 cmChiralcel OD-H column (Chiral Technologies, Inc.) eluting with 25%isopropanol in hexane (V/V) at 0.5 mL/min.

In Phase one of the complete resolution repeatedly inject 55 mg samplesof the product of Preparation 130A onto a 2.1×25 cm (R,R)Whelk-O 1column (Regis Technologies, Inc.). Elute the isomers at 10 mL/min with35% isopropanol and 0.5% acetic acid in hexane (V/V). The first of thethree peaks to elute (near 12 min) is a mixture of Isomers 1 (FormulaRRR-4 of Chart RRR) and 2 (Formula RRR-3 of Chart RRR) as shown byinjecting aliquots in System B. Resolve this mixture in Phase 2, below.

The second phase consists of a 2.1×25 cm Chiralcel OD column kept at30°. Inject 60 mg batches of the mixture obtained in the first phase andelute the enantiomers with 25% isopropanol and 0.05% trifluoroaceticacid (V/V) at 9 mL/min. Separately pooled and concentrated, thefractions eluting near 14.5 and 23.9 min to give Isomers 1 (FormulaRRR-4 where R₁ is ethyl of Chart RRR) and 2 (formula RRR-3 where R₁ isethyl of Chart RRR) respectively.

PREPARATION 147A

3-(R or S)- 1-(3-aminophenyl)-propyl!-4-hydroxy-5,6-dihydro-6-(R orS)-phenethyl-6-(R or S)-propyl-2H-pyran-2-one (Formula RRR-7; R₁ isethyl; Refer to Chart RRR)

Following the procedure of Preparation 132 beginning with the peakidentified as peak 2 (Formula RRR-3; R₁ is ethyl of Chart RRR) from thechiral resolution of the product of Preparation 147, the title compoundis prepared.

Physical characteristics are as follows:

¹ H NMR (CD₃ OD): δ6.5-7.3, 3.9-4.0, 2.5-2.7, 1.2-2.3, 0.8-1.0.

TLC (silica gel GF): Rf=0.31, 40% ethyl acetate in hexane.

EXAMPLE 335

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is5-cyanopyridine-2-yl) Isomer 1! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is phenethyl,R₂ is propyl, and R₃ is ethyl. The amine is derived from the firststereoisomer of Formula WWW-2 to elute from a Chiralcel OD chiral HPLCcolumn of Preparation 147. The title compound is obtained as anamorphous solid after flash chromatography on silica using 10% ethylacetate in dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.7-1.0, 1.2-2.6, 3.3-3.6, 6.9-7.3, 7.7-8.2, 8.8-9.0 ppm.

HRMS: 560.2210

R_(f) 0.41 (15% ethyl acetate in dichloromethane)

EXAMPLE 336

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S orR)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is5-cyanopyridine-2-yl) Isomer 2! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine that is the title product of Preparation147A (Formula WWW-3, where R₁ is phenethyl, R₂ is propyl, and R₃ isethyl). The amine is derived from the second stereoisomer of FormulaWWW-2 to elute from a Chiralcel OD chiral HPLC column of Preparation147A. The title compound is obtained as an amorphous solid after flashchromatography on silica using 10% ethyl acetate in dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.6-2.6, 3.3-3.6, 6.9-7.3, 7.7-8.2, 8.8-9.0 ppm.

HRMS: 560.2215

R_(f) 0.41 (15% ethyl acetate in dichloromethane)

EXAMPLE 337

N- 3-{1(S or R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is5-cyanopyridine-2-yl) Isomer 3! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is phenethyl,R₂ is propyl, and R₃ is ethyl. The amine is derived from the thirdstereoisomer of Formula WWW-2 to elute from a Chiralcel OD chiral HPLCcolumn of Preparation 147. The title compound is obtained as anamorphous solid after flash chromatography on silica using 10% ethylacetate in dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.6-2.6, 3.3-3.6, 6.9-7.3, 7.7-8.2, 8.8-9.0 ppm.

HRMS: 560.2210

R_(f) 0.41 (15% ethyl acetate in dichloromethane)

EXAMPLE 338

N- 3-{1(S or R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S orR)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is5-cyanopyridine-2-yl) Isomer 4! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is phenethyl,R₂ is propyl, and R₃ is ethyl. The amine is derived from the fourthstereoisomer of Formula WWW-2 to elute from a Chiralcel OD chiral HPLCcolumn of Preparation 147. The title compound is obtained as anamorphous solid after flash chromatography on silica using 10% ethylacetate in dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.7-1.0, 1.2-2.6, 3.3-3.6, 6.9-7.3, 7.7-8.2, 8.8-9.0 ppm.

HRMS: 560.2210

R_(f) 0.41 (15% ethyl acetate in dichloromethane)

EXAMPLE 339

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula WWW-4: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is1-methylimidazol-4-yl) Isomer 1! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is phenethyl,R₂ is propyl, and R₃ is ethyl. The amine is derived from the firststereoisomer of Formula WWW-2 to elute from a Chiralcel OD chiral HPLCcolumn of Preparation 147. The title compound is obtained as anamorphous solid after flash chromatography on silica using 3% methanolin dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.7-2.8, 3.2-3.7, 3.9, 7.0-7.6 ppm.

HRMS: 537.2317

R_(f) 0.36 (5% methanol in dichloromethane)

EXAMPLE 340

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S orR)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula WWW-4: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is1-methylimidazol-4-yl) Isomer 2! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is phenethyl,R₂ is propyl, and R₃ is ethyl. The amine is derived from the secondstereoisomer of Formula WWW-2 to elute from a Chiralcel OD chiral HPLCcolumn of Preparation 147. The title compound is obtained as anamorphous solid after flash chromatography on silica using 3-4% methanolin dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.7-2.7, 3.3-3.7, 4.0, 7.0-7.5 ppm.

HRMS: 537.2275

R_(f) 0.36 (5% methanol in dichloromethane)

EXAMPLE 341

N- 3-{1(S or R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula WWW-4: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is1-methylimidazol-4-yl) Isomer 3! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is phenethyl,R₂ is propyl, and R₃ is ethyl. The amine is derived from the thirdstereoisomer of Formula WWW-2 to elute from a Chiralcel OD chiral HPLCcolumn of Preparation 147. The title compound is obtained as anamorphous solid after flash chromatography on silica using 3% methanolin dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.7-2.7, 3.3-3.7, 4.0, 7.0-7.5 ppm.

HRMS: 537.2329

R_(f) 0.36 (5% methanol in dichloromethane)

EXAMPLE 342

N- 3-{1(S or R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S orR)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula WWW-4: R₁ is phenethyl, R₂ is propyl, R₃ is ethyl, R₄ is1-methylimidazol-4-yl) Isomer 4! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is phenethyl,R₂ is propyl, and R₃ is ethyl. The amine is derived from the fourthstereoisomer of Formula WWW-2 to elute from a Chiralcel OD chiral HPLCcolumn of Preparation 147. The title compound is obtained as anamorphous solid after flash chromatography on silica using 3% methanolin dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.7-2.8, 3.2-3.7, 3.9, 7.0-7.6 ppm.

HRMS: 537.2312

R_(f) 0.36 (5% methanol in dichloromethane)

PREPARATION 148

3-(3-Nitrophenyl)methyl!-6,6-diphenethyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one(Formula XXX-3) Refer to Chart XXX

To a solution of 172 mg of6,6-Diphenethyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one of formula XXX-1and 81 mg of meta-nitrobenzaldehyde in 2 ml of dry THF, under argon, isadded a solution of 142 mg of AlCl₃ in 1 ml of THF. The solution isstirred at room temperature for 2 hours, then quenched with 310 mg ofsodium carbonate decahydrate, diluted with ether, and filtered throughCelite with ether rinses. Following removal of solvent under reducedpressure, 264 mg of crude benzylidene of Formula XXX-2 is obtained. Thismaterial is dissolved in 5 ml of methanol, and the solution cooled to 0°for the addition of 44 mg of sodium cyanoborohydride. After an hour, afurther 20 mg aliquot of sodium cyanoborohydride is added. After another30 minutes, the mixture is acidified with dilute HCl to pH 1 andextracted with three portions of dichloromethane. The extract is dried(MgSO₄) and then concentrated under reduced pressure. Flashchromatography of the residue on silica using 5-20% ethyl acetate indichloromethane provides 211 mg of the title compound as an amorphouswhite solid.

Physical characteristics are as follows:

¹ H NMR δ2.0, 2.7, 3.8, 7.0-7.4, 7.6, 8.0, 8.2 ppm.

MS: M+ 457

R_(f) 0.25 (5% ethyl acetate in dichloromethane)

PREPARATION 149

3-(3-Aminophenyl)methyl!-6,6-diphenethyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one(Formula XXX-4) Refer to Chart XXX

A mixture of 211 mg of the product of Preparation 148 (Formula XXX-3)and 50 mg of 10% palladium on carbon in 5 ml of methanol is stirred atroom temperature under 1 atmosphere hydrogen gas. After two hours, themixture is filtered through Celite and concentrated under reducedpressure. Flash chromatography of the residue on silica using 25% ethylacetate in dichloromethane affords 133.6 mg of the title compound.

Physical characteristics are as follows:

¹ H NMR δ2.0, 2.6, 3.6, 4.1, 6.5, 6.6, 6.7, 6.9-7.3 ppm.

MS: M+ 427

R_(f) 0.33 (25% ethyl acetate in dichloromethane)

EXAMPLE 343

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula YYY-5) R₁ and R₂ are phenethyl, R₃ is 1-methylimidazole-4-yl)Refer to Chart YYY

Using the general sulfonylation procedure of Example 252, 77 mg of theamine of formula YYY-4 (R₁ and R₂ are phenethyl) is reacted with1-methylimidazole-4-sulfonyl chloride. Flash chromatography on silicausing 3% methanol in dichloromethane provides 90.7 mg of the titlecompound as an amorphous white solid.

Physical characteristics are as follows:

¹ H NMR δ0.96, 1.0, 1.6-2.7, 3.45, 6.8-7.5 ppm.

HRMS: 628.2832

R_(f) 0.38 (3% methanol in dichloromethane)

EXAMPLE 344

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula YYY-5) R₁ and R₂ are phenethyl, R₃ is 5-cyanopyridine-2-yl)Refer to Chart YYY

Using the general sulfonylation procedure of Example 252, 77 mg of theamine of Formula YYY-4 (R₁ and R₂ are phenethyl) is reacted with5-cyanopyridine-2-sulfonyl chloride. Flash chromatography on silicausing 10% ethyl acetate in dichloromethane provides 86.1 mg of the titlecompound as an amorphous white solid.

Physical characteristics are as follows:

¹ H NMR δ0.96, 1.8-2.2, 2.5-2.8, 4.1, 4.3, 6.9-7.4, 7.9-8.0, 8.9 ppm.

HRMS: 650.2681

R_(f) 0.27 (10% ethyl acetate in dichloromethane)

PREPARATION 150

Resolution of N- 3-1-(4-Hydroxy-5,6-dihydro-2-oxo-6-(2-(4-fluorophenyl)ethyl-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl!phenyl!carbamicacid, phenylmethyl ester to give 4 isomers (Formula WWW-2: R₁ is4-fluorophenethyl, R₂ is propyl, R₃ is t-butyl) Refer to Chart WWW

System C is used to track the enantiomers and to monitor the preparativecolumns. System C consists of a 0.46×25 cm Chiralcel OD-H column (ChiralTechnologies, Inc.) with 15% isopropanol in hexane (V/V) at 0.5 mL/min.The peaks eluting near 13.5, 18.8, 37.1 and 79.7 min are, respectively,Isomer 1, Isomer 2, Isomer 3, and Isomer 4.

Separate Isomers 3 and 4 from the mixture on a 2.1×25 cm (R,R)Whelk-O 1column (Regis Technologies, Inc.). These two isomers elute at about 23.9and 26.8 min when the column is developed with 20% isopropanol in hexane(V/V) at 10 mL/min at 30°. The desired isomers elute as an unresolvedmixture near 28.9 min and are separated in the second stage of theresolution.

For the second stage inject the unresolved mixture onto a 2.1×25 cmChiralcel OD column (Chiral technologies, Inc.) kept at 30°. With 12%isopropanol in hexane (V/V) at 12 mL/min, Isomer 1 emerges near 14.5 minand Isomer 2 emerges near 20.8 min.

EXAMPLE 345

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4: R₁ is 4-fluorophenethyl, R₂ is propyl, R₃ is tert-butyl,R₄ is 5-cyanopyridine-2-yl) Isomer 1! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is4-fluorophenethyl, R₂ is propyl, and R₃ is ethyl. The amine is derivedfrom the first stereoisomer of Formula WWW-2 to elute from a ChiralcelOD chiral HPLC column of Preparation 150. The title compound is obtainedas an amorphous solid after flash chromatography on silica using 10%ethyl acetate in dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.7-2.7, 3.2, 3.5, 3.6, 3.7, 4.1, 6.8-7.4, 7.5, 7.8-8.2, 8.8ppm.

HRMS: 606.2429

R_(f) 0.40 (15% ethyl acetate in dichloromethane)

EXAMPLE 346

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S orR)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4: R₁ is 4-fluorophenethyl, R₂ is propyl, R₃ is tert-butyl,R₄ is 5-cyanopyridine-2-yl) Isomer 2! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is4-fluorophenethyl, R₂ is propyl, and R₃ is ethyl. The amine is derivedfrom the second stereoisomer of Formula WWW-2 to elute from a ChiralcelOD chiral HPLC column of Preparation 150. The title compound is obtainedas an amorphous solid after flash chromatography on silica using 10%ethyl acetate in dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.6, 0.7-2.6, 3.4, 3.5, 3.7, 4.2, 6.8-7.3, 7.5, 7.8-8.2,8.8-9.0 ppm.

MS: 606.2434

R_(f) 0.40 (15% ethyl acetate in dichloromethane)

EXAMPLE 347

N- 3-{1(S or R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethyl-propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4: R₁ is 4-fluorophenethyl, R₂ is propyl, R₃ is tert-butyl,R₄ is 5-cyanopyridine-2-yl) Isomer 3! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is4-fluorophenethyl, R₂ is propyl, and R₃ is ethyl. The amine is derivedfrom the third stereoisomer of Formula WWW-2 to elute from a ChiralcelOD chiral HPLC column of Preparation 150. The title compound is obtainedas an amorphous solid after flash chromatography on silica using 10%ethyl acetate in dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.6, 0.7-2.6, 3.4, 3.5, 3.7, 4.2, 6.8-7.3, 7.5, 7.8-8.2,8.8-9.0 ppm.

MS: 606.2423

R_(f) 0.40 (15% ethyl acetate in dichloromethane)

EXAMPLE 348

N- 3-{1(S or R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S orR)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4: R₁ is 4-fluorophenethyl, R₂ is propyl, R₃ is tert-butyl,R₄ is 5-cyanopyridine-2-yl) Isomer 4! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is4-fluorophenethyl, R₂ is propyl, and R₃ is ethyl. The amine is derivedfrom the fourth stereoisomer of Formula WWW-2 to elute from a ChiralcelOD chiral HPLC column of Preparation 150. The title compound is obtainedas an amorphous solid after flash chromatography on silica using 10%ethyl acetate in dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.7-2.7, 3.2, 3.5, 3.6, 3.7, 4.1, 6.8-7.4, 7.5, 7.8-8.2, 8.8ppm.

HRMS: 606.2429

R_(f) 0.40 (15% ethyl acetate in dichloromethane)

EXAMPLE 349

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula WWW-4: R₁ is 4-fluorophenethyl, R₂ is propyl, R₃ is tert-butyl,R₄ is 1-methylimidazol-4-yl Isomer 1! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is4-fluorophenethyl, R₂ is propyl, and R₃ is ethyl. The amine is derivedfrom the first stereoisomer of Formula WWW-2 to elute from a ChiralcelOD chiral HPLC column of Preparation 150. The title compound is obtainedas an amorphous solid after flash chromatography on silica using 3%methanol in dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.8-1.0, 1.4, 1.7, 2.3-2.7, 3.6, 3.9, 4.1, 6.8-7.5 ppm.

HRMS: 584.2585

R_(f) 0.34 (5% methanol in dichloromethane)

EXAMPLE 350

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S orR)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula WWW-4: R₁ is 4-fluorophenethyl, R₂ is propyl, R₃ is tert-butyl,R₄ is 1-methylimidazol-4-yl Isomer 2! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is4-fluorophenethyl, R₂ is propyl, and R₃ is ethyl. The amine is derivedfrom the second stereoisomer of Formula WWW-2 to elute from a ChiralcelOD chiral HPLC column of Preparation 150. The title compound is obtainedas an amorphous solid after flash chromatography on silica using 3%methanol in dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.7-1.1, 1.3, 1.7, 2.3-2.7, 3.6, 3.9, 4.1, 6.8-7.5 ppm.

HRMS: 584.2585

R_(f) 0.34 (5% methanol in dichloromethane)

EXAMPLE 351

N- 3-{1(S or R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula WWW-4: R₁ is 4-fluorophenethyl, R₂ is propyl, R₃ is tert-butyl,R₄ is 1-methylimidazol-4-yl Isomer 3! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is4-fluorophenethyl, R₂ is propyl, and R₃ is ethyl. The amine is derivedfrom the third stereoisomer of Formula WWW-2 to elute from a ChiralcelOD chiral HPLC column of Preparation 150. The title compound is obtainedas an amorphous solid after flash chromatography on silica using 3%methanol in dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.7-1.1, 1.3, 1.7, 2.3-2.7, 3.6, 3.9, 4.1, 6.8-7.5 ppm.

HRMS: 584.2591

R_(f) 0.34 (5% methanol in dichloromethane)

EXAMPLE 352

N- 3-{1(S or R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S orR)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula WWW-4: R₁ is 4-fluorophenethyl, R₂ is propyl, R₃ is tert-butyl,R₄ is 1-methylimidazol-4-yl Isomer 4! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ is4-fluorophenethyl, R₂ is propyl, and R₃ is ethyl. The amine is derivedfrom the fourth stereoisomer of Formula WWW-2 to elute from a ChiralcelOD chiral HPLC column of Preparation 150. The title compound is obtainedas an amorphous solid after flash chromatography on silica using 3%methanol in dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.8-1.0, 1.4, 1.7, 2.3-2.7, 3.6, 3.9, 4.1, 6.8-7.5 ppm.

HRMS: 584.2580

R_(f) 0.34 (5% methanol in dichloromethane)

EXAMPLE 353

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)methyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula XXX-5, R₁ is 5-cyanopyridine-2-yl) Refer to Chart XXX

Using the general sulfonylation procedure of Example 252, 64 mg of theamine of formula XXX-4 is reacted with 5-cyanopyridine-2-sulfonylchloride. Flash chromatography on silica using 2-3% methanol indichloromethane provides 73.2 mg of the title compound as an amorphouswhite solid.

Physical characteristics are as follows:

¹ H NMR δ1.8-2.1, 2.6, 6.9-7.3, 7.9, 8.8 ppm.

HRMS: 594.2068

R_(f) 0.40 (3% methanol in dichloromethane)

EXAMPLE 354

N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)methyl}phenyl!-5-aminopyridine-2-sulfonamide(Formula UUU-6, R₁ and R₂ are phenethyl, R₃ is H). Refer to Chart UUU

Using the general sulfonylation procedure of Example 252, 69 mg of theamine of formula XXX-4 is reacted with 5-nitropyridine-2-sulfonylchloride. Flash chromatography on silica using 2-3% methanol indichloromethane provides 107 mg of the intermediate nitro compound offormula UUU-5 (R₁ and R₂ are phenethyl, R₃ is H). Reduction to the amineis accomplished using hydrogen gas and palladium on carbon catalyst.Flash chromatography on silica gel using 4-6% methanol indichloromethane provides 65.0 mg of the title compound as an amorphouswhite solid.

Physical characteristics are as follows:

¹ H NMR δ1.9-2.1, 2.6, 3.5-4.0, 6.7, 6.9-7.3, 7.5, 7.9 ppm.

HRMS: 584.2215

R_(f) 0.24 (5% methanol in dichloromethane)

PREPARATION 151

Resolution of N- 3-1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl!phenyl!carbamicacid, phenylmethyl ester to give 2 enantiomers (Formula WWW-2: R₁ and R₂are phenethyl, R₃ is t-butyl) Refer to Chart WWW

Inject 40 mg batches of the starting compound onto a 2.1×25 cm(R,R)Whelk-O 1 column (Regis Technologies, Inc.) that is maintained at30°. The 2 enantiomers elute at about 37 min (Enantiomer 1) and 43 min(Enantiomer 2) using 25% isopropanol and 0.05% acetic acid at 12 mL/min.Fractions are pooled on the basis of results from analysis on a 0.46×25cm (R,R)Whelk-O 1 column eluted with 30% isopropanol and 0.1% aceticacid (V/V) at 1.0 mL/min. The isomers elute at (Isomer 1) 19.1 and(Isomer 2) 23.0 min respectively.

EXAMPLE 355

N- 3-{1(R orS)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-aminopyridine-2-sulfonamide(Formula WWW-4, R₁ and R₂ are phenethyl, R₃ is tert-butyl, R₄ is5-aminopyridine-2-yl) Enantiomer 1! Refer to Chart WWW

Using the general sulfonylation procedure of Example 252, 73 mg of theamine of Formula WWW-3 (R₁ and R₂ are phenethyl, R₃ is tert-butyl) isreacted with 5-nitropyridine-2-sulfonyl chloride. The amine used isderived from the first enantiomer of Formula WWW-2 to elute from an(R,R)Whelk-O chiral HPLC column of Preparation 151. Flash chromatographyon silica using 5-10% ethyl acetate in dichloromethane provides 94.0 mgof the intermediate nitro compound of formula UUU-5 (R₁ and R₂ arephenethyl, R₃ is tert-butyl). Reduction to the amine is accomplishedusing hydrogen gas and palladium on carbon catalyst. Flashchromatography on silica gel using 4% methanol in dichloromethaneprovides 74.8 mg of the title compound as an amorphous white solid.

Physical characteristics are as follows:

¹ H NMR δ0.95, 2.0, 2.6, 6.8, 6.9-7.4, 7.5, 7.9 ppm.

HRMS: 640.2828

R_(f) 0.27 (5% methanol in dichloromethane)

EXAMPLE 356

N- 3-{1(S orR)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-aminopyridine-2-sulfonamide(Formula WWW-4, R₁ and R₂ are phenethyl, R₃ is tert-butyl, R₄ is5-aminopyridine-2-yl) Enantiomer 2! Refer to Chart WWW

Using the general sulfonylation procedure of Example 252, 73 mg of theamine of Formula WWW-3 (R₁ and R₂ are phenethyl, R₃ is tert-butyl) isreacted with 5-nitropyridine-2-sulfonyl chloride. The amine used isderived from the second enantiomer of Formula WWW-2 to elute from an(R,R)Whelk-O chiral HPLC column of Preparation 151. Flash chromatographyon silica using 5-10% ethyl acetate in dichloromethane provides 91.3 mgof the intermediate nitro compound of formula UUU-5 (R₁ and R₂ arephenethyl, R₃ is tert-butyl). Reduction to the amine is accomplishedusing hydrogen gas and palladium on carbon catalyst. Flashchromatography on silica gel using 4% methanol in dichloromethaneprovides 54.3 mg of the title compound as an amorphous white solid.

Physical characteristics are as follows:

¹ H NMR δ0.95, 2.0, 2.6, 6.8, 6.9-7.4, 7.5, 7.9 ppm.

HRMS: 640.2828

R_(f) 0.27 (5% methanol in dichloromethane)

EXAMPLE 357

N- 3-{1(R orS)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula WWW-4, R₁ and R₂ are phenethyl, R₃ is tert-butyl, R₄ is1-methylimidazol-4-yl) Enantiomer 1! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ and R₂ arephenethyl and R₃ is tert-butyl. The amine is derived from the firstenantiomer of Formula WWW-2 to elute from an (R,R)Whelk-O chiral HPLCcolumn of Preparation 151. The title compound is obtained as anamorphous solid after flash chromatography on silica using 3% methanolin dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.98, 2.0, 2.6, 3.6, 3.8, 6.9-7.5 ppm.

HRMS: 628.2832

R_(f) 0.38 (5% methanol in dichloromethane)

EXAMPLE 358

N- 3-{1(S orR)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula WWW-4, R₁ and R₂ are phenethyl, R₃ is tert-butyl, R₄ is1-methylimidazol-4-yl) Enantiomer 2! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ and R₂ arephenethyl and R₃ is tert-butyl. The amine is derived from the secondenantiomer of Formula WWW-2 to elute from an (R,R)Whelk-O chiral HPLCcolumn of Preparation 151. The title compound is obtained as anamorphous solid after flash chromatography on silica using 3% methanolin dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.98, 2.0, 2.6, 3.6, 3.8, 6.9-7.5 ppm.

HRMS: 628.2838

R_(f) 0.38 (5% methanol in dichloromethane)

EXAMPLE 359

N- 3-{1(R orS)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4, R₁ and R₂ are phenethyl, R₃ is tert-butyl, R₄ is5-cyanopyridine-2-yl) Enantiomer 1! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ and R₂ arephenethyl and R₃ is tert-butyl. The amine is derived from the firstenantiomer of Formula WWW-2 to elute from an (R,R)Whelk-O chiral HPLCcolumn of Preparation 151. The title compound is obtained as anamorphous solid after flash chromatography on silica using 10% ethylacetate in dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.87, 1.9, 2.6, 6.8-7.4, 7.9, 8.8 ppm.

HRMS: 650.2681

R_(f) 0.46 (15% ethyl acetate in dichloromethane)

EXAMPLE 360

N- 3-{1(S orR)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4, R₁ and R₂ are phenethyl, R₃ is tert-butyl, R₄ is5-cyanopyridine-2-yl) Enantiomer 2! Refer to Chart WWW

The title compound is prepared using the general sulfonylation procedureof Example 252, using the amine of Formula WWW-3, where R₁ and R₂ arephenethyl and R₃ is tert-butyl. The amine is derived from the secondenantiomer of Formula WWW-2 to elute from an (R,R)Whelk-O chiral HPLCcolumn of Preparation 151. The title compound is obtained as anamorphous solid after flash chromatography on silica using 10% ethylacetate in dichloromethane.

Physical characteristics are as follows:

¹ H NMR δ0.87, 1.9, 2.6, 6.8-7.4, 7.9, 8.8 ppm.

HRMS: 650.2681

R_(f) 0.46 (15% ethyl acetate in dichloromethane)

PREPARATION 152

Resolution of N- 3-1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-propyl!phenyl!carbamicacid, phenylmethyl ester to give 2 isomers (Formula WWW-2: R₁ and R₂ arepropyl, R₃ is ethyl) Refer to Chart WWW

Samples of the starting compound are injected onto a 2.1×25 cm ChiralcelOD column and eluted with 20% isopropanol (V/V) in hexane at 10 mL/min.The material eluting near 19.1 minutes is one isomer (Enantiomer 1) andthat eluting near 37.7 minutes is another isomer (Enantiomer 2). Thepools are concentrated separately on a rotary evaporator (ca. 30 mm,bath at 50° maximum) to give white solids.

EXAMPLE 361

N- 3-{1(R orS)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4, R₁ and R₂ are propyl, R₃ is ethyl, R₄ is5-cyanopyridine-2-yl) Enantiomer 1! Refer to Chart WWW

Following procedures analogous to those described above, but usingEnantiomer 1 of Preparation 152, the title compound is obtained.

Physical characteristics are as follows:

¹ H NMR δ0.8-1.0, 1.2-2.2, 3.90, 6.9-7.2, 8.0, 8.15, 8.9 ppm.

HRMS: 497.1984

R_(f) 0.38 (15% ethyl acetate in dichloromethane)

EXAMPLE 362

N- 3-{1(S orR)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4, R₁ and R₂ are propyl, R₃ is ethyl, R₄ is5-cyanopyridine-2-yl) Enantiomer 2! Refer to Chart WWW

Following procedures analogous to those described above, but usingEnantiomer 2 of Preparation 152, the title compound is obtained.

Physical characteristics are as follows:

¹ H NMR δ0.8-1.0, 1.2-2.2, 3.90, 6.9-7.2, 8.0, 8.15, 8.9 ppm.

HRMS: 497.1980

R_(f) 0.38 (15% ethyl acetate in dichloromethane)

EXAMPLE 363

N- 3-{1(R orS)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-propyl}phenyl!-5-aminopyridine-2-sulfonamide(Formula WWW-4, R₁ and R₂ are propyl, R₃ is ethyl, R₄ is5-aminopyridine-2-yl) Enantiomer 1! Refer to Chart WWW

Following procedures analogous to those described above, but usingEnantiomer 1 of Preparation 152, the title compound is obtained.

Physical characteristics are as follows:

¹ H NMR δ0.7-0.9, 1.2-2.2, 3.8, 6.8-7.2, 7.5, 7.9 ppm.

HRMS: 487.2122

R_(f) 0.28 (5% methanol in dichloromethane)

EXAMPLE 364

N- 3-{1(S orR)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-propyl}phenyl!-5-aminopyridine-2-sulfonamide(Formula WWW-4, R₁ and R₂ are propyl, R₃ is ethyl, R₄ is5-aminopyridine-2-yl) Enantiomer 2! Refer to Chart WWW

Following procedures analogous to those described above, but usingEnantiomer 2 of Preparation 152, the title compound is obtained.

Physical characteristics are as follows:

¹ H NMR δ0.7-0.9, 1.2-2.2, 3.8, 6.8-7.2, 7.5, 7.9 ppm.

HRMS: 487.2140

R_(f) 0.28 (5% methanol in dichloromethane)

PREPARATION 153

Resolution of N- 3-1-(4-Hydroxy-5,6-dihydro-2-oxo-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl!-phenyl!carbamicacid, phenylmethyl ester to give 4 isomers (Formula WWW-2: R₁ is4-fluorophenethyl, R₂ is propyl, and R₃ is ethyl) Refer to Chart WWW

The enantiomers are defined by elution order from System D. HPLC SystemD consists of a 0.46×25 cm Chiralcel OD-H column (Chiral Technologies,Inc.) with 20% isopropanol and 0.05% trifluoroacetic acid in hexane(V/V) pumped at 0.5 mL/min. The retention times in this system are(Isomer 1) 21.6, (Isomer 2) 34.5, (Isomer 3) 55.2 and (Isomer 4) 66.6min.

Separate the enantiomers on a 2.1×25 cm Chiralcel OD column (ChiralTechnologies, Inc.). Aliquots are injected and the enantiomers elutedwith 17.5% isopropanol in hexane (V/V) at 10 mL/min. Fractions elutingnear 24.6, 42.9, 66.3 and 77.4 min are pooled appropriately after assaywith System D. In order of elution, the four isomers are designatedIsomers 1-4, respectively.

In all cases, whenever solvent is stripped from a pool the followingprotocol is used: Solvent is removed from pools of fractions on a rotaryevaporator with house vacuum (ca. 30 mm Hg) and a water bath set at45°±5°. If acetic acid is present in the solvent, add ca. 10 mL oftoluene/L of pool before the flask goes dry. Residues are then washedinto tared flasks using methylene chloride and the solvent is strippedas above. Final solvent removal is accomplished at ambient temperature,1 mmHg pressure for 2-24 hours before weighing.

EXAMPLE 365

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4: R₁ is 4-fluorophenethyl, R₂ is propyl, R₃ is ethyl, R₄is 5-cyanopyridine-2-yl) Isomer 1! Refer to Chart WWW

Following procedures analogous to those described above, but usingIsomer 1 of Preparation 153, the title compound is obtained.

Physical characteristics are as follows:

¹ H NMR δ0.8-1.0, 1.3, 1.6-2.2, 2.5, 3.9, 6.8-7.3, 7.9-8.1, 8.9 ppm.

HRMS: 578.2120

R_(f) 0.35 (15% ethyl acetate in dichloromethane)

EXAMPLE 366

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S orR)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4: R₁ is 4-fluorophenethyl, R₂ is propyl, R₃ is ethyl, R₄is 5-cyanopyridine-2-yl) Isomer 2! Refer to Chart WWW

Following procedures analogous to those described above, but usingIsomer 2 of Preparation 153, the title compound is obtained.

Physical characteristics are as follows:

¹ H NMR δ0.8-1.0, 1.3, 1.6-2.2, 2.5, 3.9, 6.8-7.3, 7.9-8.1, 8.9 ppm.

HRMS: 578.2120

R_(f) 0.35 (15% ethyl acetate in dichloromethane)

EXAMPLE 367

N- 3-{1(S or R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4: R₁ is 4-fluorophenethyl, R₂ is propyl, R₃ is ethyl, R₄is 5-cyanopyridine-2-yl) Isomer 3! Refer to Chart WWW

Following procedures analogous to those described above, but usingIsomer 3 of Preparation 153, the title compound is obtained.

Physical characteristics are as follows:

¹ H NMR δ0.8-1.0, 1.3, 1.6-2.2, 2.5, 3.9, 6.8-7.3, 7.9-8.1, 8.9 ppm.

HRMS: 578.2126

R_(f) 0.35 (15% ethyl acetate in dichloromethane)

EXAMPLE 367A

N- 3-{1(S or R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S orR)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide(Formula WWW-4: R₁ is 4-fluorophenethyl, R₂ is propyl, R₃ is ethyl, R₄is 5-cyanopyridine-2-yl) Isomer 4! Refer to Chart WWW

Following procedures analogous to those described above, but usingIsomer 4 of Preparation 153, the title compound is obtained.

Physical characteristics are as follows:

¹ H NMR δ0.8-1.0, 1.3, 1.6-2.2, 2.5, 3.9, 6.8-7.3, 7.9-8.1, 8.9 ppm.

HRMS: 578.2126

R_(f) 0.35 (15% ethyl acetate in dichloromethane)

EXAMPLE 368

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide(Formula WWW-4: R₁ is 4-fluorophenethyl, R₂ is propyl, R₃ is ethyl, R₄is 1-methylimidazol-4-yl) Isomer 1! Refer to Chart WWW

Following procedures analogous to those described above, but usingIsomer 1 of Preparation 153, the title compound are as follows:

Physical characteristics are as follows:

¹ H NMR δ0.8-1.0, 1.3, 1.6-2.2, 2.6, 3.63, 4.0, 6.9-7.5 ppm.

HRMS: 556.2265

R_(f) 0.29 (5% methanol in dichloromethane)

EXAMPLE 369

N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-aminopyridine-2-sulfonamide(Formula WWW-4: R₁ is 4-fluorophenethyl, R₂ is propyl, R₃ is ethyl, R₄is 5-aminopyridine-2-yl) Isomer 1! Refer to Chart WWW

Following procedures analogous to those described above, but usingIsomer 1 of Preparation 153, the title compound is obtained.

Physical characteristics are as follows:

¹ H NMR δ0.8-1.0, 1.3, 1.6-2.2, 2.5, 3.9, 6.8-7.2, 7.5, 7.9 ppm.

HRMS: 568.2271

R_(f) 0.27 (5% methanol in dichloromethane)

PREPARATION 154

Hexahydro-2H-1-benzopyran-2,4(3H)-dione (Formula DDDD-2, wherein n is 1)Refer to Chart DDDD

A solution of 0.42 g of platinum oxide and 1.66 g of the compound offormula DDDD-1 wherein n is 1 in 100 mL of acetic acid is placed on aParr hydrogenation apparatus under an initial pressure of 50 psi ofhydrogen for 1.5 h. The reaction mixture is then filtered through Celiteand concentrated in vacuo to give a beige solid. The crude material ispurified by flash column chromatography on silica gel 60 (230-400 mesh)eluting with 0-5% methanol in chloroform to give 0.94 g of the titleproduct as a white solid.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ4.84-4.80, 3.54, 3.40, 2.60-2.53, 2.08-2.02, 1.79-1.65,1.62-1.54, 1.44-1.40 ppm.

¹³ C NMR (CDCl₃) δ203.0, 167.4, 74.3, 47.7, 45.6, 29.1, 23.5, 23.2, 19.7ppm.

IR (mineral oil) 3092, 2768, 2714, 2695, 2662, 1657, 1614, 1577, 1444,1352, 1345, 1340, 1323, 1308, 1295, 1287, 1260, 1244, 1211, 1188, 1057,1004, 938, 909, 890, 843, 832, 600 cm⁻¹.

EI-MS: M+!=168.

Anal. found: C, 64.16; H, 7.16.

PREPARATION 155

4a,5,6,7,8,8a-Hexahydro-4-hydroxy-3-1-(3-nitrophenyl)propyl!-2H-1-benzopyran-2-one (Formula DDDD-4, whereinn is 1 and R₁ is ethyl) Refer to Chart DDDD

A solution of 3.17 g of aluminum trichloride in 30 mL of tetrahydrofuranis added to a solution of 2.00 g of the title compound of Preparation154 and 1.82 g of 3-nitrobenzaldehyde in 20 mL of tetrahydrofuran. Theresulting mixture is then stirred at room temperature for 2.5 h, atwhich time, 7.28 g of sodium carbonate decahydrate is added, and thereaction mixture is stirred an additional 20 min. The mixture is thendried over magnesium sulfate, filtered through Celite, and concentratedin vacuo to yield 6.05 g of a yellow gum. This crude material isimmediately dissolved in 50 mL of tetrahydrofuran containing 0.73 g ofcuprous bromide-dimethyl sulfide complex, and 13.1 mL of a 1.0M solutionof triethyl aluminum in hexanes are added to the reaction mixture. Afterstirring at room temperature for 1 h, the reaction is quenched by theaddition of water, and the resulting mixture is partitioned betweenether and water. The organic layer is separated, washed with brine, andconcentrated in vacuo to produce 4.0 g of a yellow oil. The crudematerial is purified by flash column chromatography eluting with 10-50%ethyl acetate in hexanes to yield 0.63 g of the title product as ayellow foam.

Physical characteristics are as follows:

MP 86°-91° C.

IR (mineral oil) 3085, 1635, 1569, 1528, 1448, 1394, 1365, 1349, 1325,1307, 1288, 1270, 1251, 1244 cm⁻¹.

EXAMPLE 370

5-Cyano-N-3-1-(4a,5,6,7,8,8a-hexahydro-4-hydroxy-2-oxo-2H-1-benzopyran-3-yl)propyl!phenyl!-2-pyridinesulfonamide(Formula DDDD-7, wherein n is 1, R₁ is ethyl, and R₂ is5-cyano-2-pyridyl) Refer to Chart DDDD

A solution of 0.63 g of the title compound of Preparation 155 in 50 mLof ethanol with 0.3 g of 10% palladium on carbon is placed on a Parrhydrogenation apparatus at an initial pressure of 50 psi of hydrogen for3 h. The reaction mixture is then filtered through Celite andconcentrated in vacuo to give 0.519 g of crude intermediate. 0.25 g ofthis intermediate is immediately dissolved in 5 mL of methylenechloride, and 0.168 g of 5-cyano-2-pyridylsulfonyl chloride and 0.134 mLof pyridine are added to the solution. The resulting mixture is stirredat room temperature for 18 h. The reaction mixture is then purified byflash column chromatography on silica gel 60 (230-400 mesh) eluting with0-2.5% methanol in chloroform to give 0.164 g of the title product as awhite foam.

Physical characteristics are as follows:

MP 122°-125° C.

HRMS found: 468.1611

EXAMPLE 371

4-Cyano-N-3-1-(4a,5,6,7,8,8a-hexahydro-4-hydroxy-2-oxo-2H-1-benzopyran-3-yl)propyl!phenyl!-benzenesulfonamide(Formula DDDD-7, wherein n is 1, R₁ is ethyl, and R₂ is 4-cyanophenyl)Refer to Chart DDDD

Following the general procedure of Example 370, and making non-criticalvariations, but substituting 4-cyanophenylsulfonyl chloride for5-cyano-2-pyridylsulfonyl chloride, 0.236 g of the title compound isobtained as white foam.

Physical characteristics are as follows:

MP 127°-130° C.

HRMS found: 466.1583.

PREPARATION 156

4-Hexahydro-cyclohepta b!pyran-2,4(3H,4aH)-dione (Formula DDDD-2,wherein n is 2) Refer to Chart DDDD

Following the general procedure of Preparation 154, and makingnon-critical variations, but substituting the cycloheptylpyranone ofFormula DDDD-1 wherein n is 2 for the cyclohexylpyranone of FormulaDDDD-1 wherein n is 1, 0.337 g of the title compound is obtained aswhite solid.

Physical characteristics are as follows:

¹ H NMR CDCl₃) δ4.97-4.91, 3.52, 3.42, 2.64-2.58, 2.22-2.11, 2.01-1.72,1.59-1.36 ppm.

¹³ C NMR (CDCl₃) δ203.0, 167.2, 78.0, 52.1, 46.5, 32.1, 28.6, 27.1,25.7, 21.3 ppm.

IR (mineral oil) 3074, 2791, 2755, 2736, 2687, 2637, 2608, 2585, 1655,1625, 1586, 1500, 1480, 1443, 1333, 1324, 1293 (s), 1265, 1254, 1240,1222, 1196, 1173, 1082, 1053, 1016, 909, 889, 832, 611 cm⁻¹.

EI-MS: M+!=182.

Anal. found: C, 66.16; H, 7.90.

PREPARATION 157

5,6,7,8,9,9a-Hexahydro-4-hydroxy-3- 1-(3-nitrophenyl)-propyl!-cycloheptab!pyran-2(4aH)-one (Formula DDDD-4, wherein n is 2 and R₁ is ethyl)Refer to Chart DDDD

Following the general procedure of Preparation 155, and makingnon-critical variations, but substituting the title compound ofPreparation 156 for the title compound of Preparation 154, 2.5 g of thetitle compound is obtained as a yellow foam.

Physical characteristics are as follows:

MP 75°-78° C.

IR (mineral oil) 3071, 2667, 1638, 1528, 1395, 1350, 1305, 1276, 1250,1143, 1130, 1120, 1100, 1066, 782, 764, 741, 697, 685 cm⁻¹.

HRMS found: 345.1590.

Anal. found: C, 58.74; H, 5.63; N, 3.48.

EXAMPLE 372

5-Cyano-N- 3- 1-(2,4a,5,6,7,8,9,9a-octahydro-4-hydroxy-2-oxocycloheptab!pyran-3-yl)propyl!phenyl!-2-pyridinesulfonamide (Formula DDDD-7,wherein n is 2, R₁ is ethyl, and R₂ is 5-cyano-2-pyridyl) Refer to ChartDDDD

Following the general procedure of Example 370, and making non-criticalvariations, but substituting the title compound of Preparation 157 forthe title compound of Preparation 155, 0.206 g of the title compound isobtained as a white foam.

Physical characteristics are as follows:

MP 163°-166° C.

IR (mineral oil) 3352, 3128, 3100, 3073, 3029, 1760, 1726, 1641, 1608,1593, 1584, 1411, 1397, 1355, 1295, 1282, 1242, 1207, 1173, 1125, 1106,1086, 1074, 1028, 974, 967, 721, 701, 645, 638 cm⁻¹.

HRMS found: 481.1693.

PREPARATION 158

Octahydro-2H-cycloocta b!pyran-2,4(3H)-dione (Formula DDDD-2, wherein nis 3) Refer to Chart DDDD

Following the general procedure of Preparation 154, and makingnon-critical variations, but substituting the cyclooctylpyranone ofFormula DDDD-1 wherein n=3 for the cycloheptylpyranone of Formula DDDD-1wherein n=2, 1.72 g of the title compound is obtained as a white solid.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ4.84-4.78, 3.61, 3.40, 2.75-2.70, 2.14-1.97, 1.90-1.72,1.68-1.44 ppm.

¹³ C NMR (CDCl₃) δ204.2, 167.2, 78.2, 49.5, 46.1, 28.5, 27.3, 26.2,24.7, 23.9, 22.1 ppm.

IR (mineral oil) 2659, 2617, 1650, 1612, 1579, 1444, 1356, 1332, 1307,1287, 1265, 1244, 1227, 1209, 1041, 1035, 1003, 962, 946, 860, 832, 824cm⁻¹.

HRMS found: 196.1100.

Anal. found: C, 67.06; H, 8.23.

PREPARATION 159

3-2,2-Dimethyl-1-(3-nitrophenyl)propyl!-4a,5,6,7,8,9,10,10a-octahydro-4-hydroxy-2H-cyclooctab!pyran-2-one (Formula DDDD-4, wherein n is 3 and R₁ is t-butyl) Referto Chart DDDD

A solution of 1.36 g of aluminum trichloride in 30 mL of tetrahydrofuranis added to a solution of 1.0 g of the title compound of Preparation 158and 0.77 g of 3-nitrobenzaldehyde in 20 mL of tetrahydrofuran. Theresulting mixture is then stirred at room temperature for 2.3 h, atwhich time, 3.06 g of sodium carbonate decahydrate is added, and thereaction mixture is stirred an additional 15 min. The mixture is thendried over magnesium sulfate, filtered through Celite, and concentratedin vacuo to yield a yellow foam. This crude intermediate is immediatelydissolved in 5 mL of tetrahydrofuran for use in the second step.

A dry flask is charged with 0.82 g of activated zinc, 3 mL oftetrahydrofuran, 0.035 mL of dibromoethane, and 0.21 mL of a 1M solutionof trimethylsilyl chloride in tetrahydrofuran. After the addition ofeach reagent the mixture is sonicated for 15 m at 45° C. The mixture isdiluted further by the addition of 2 mL tetrahydrofuran and 1.32 mL oft-butyl iodide is added dropwise. The resulting mixture is sonicated for3 h at 45° C. A separate mixture of 0.85 g of copper(I) cyanide and 0.80g of lithium chloride in 4 mL of tetrahydrofuran is stirred at roomtemperature for 1 h until almost homogeneous and cooled to -30° C. Theorganozinc solution is then added via cannula to the copper cyanidesolution and the resulting mixture is allowed to warm to 0° C. and tostir for 15 min. The reaction mixture is then cooled to -78° C., and thesolution of crude intermediate prepared above is added. After stirringfor 20 min at -78° C. and 30 min at 0° C., the reaction is quenched witha saturated solution of aqueous ammonium chloride and diluted with anadditional 60 mL of tetrahydrofuran. The organic layer is separated,washed with water, and concentrated in vacuo to give 2.17 g of an orangefoam. The crude material is then purified by flash column chromatographyeluting with 10-30% ethyl acetate in hexanes followed byrecrystallization in methylene chloride/hexanes to yield 0.60 g of thetitle product as a yellow solid.

Physical characteristics are as follows:

MP 158°-161° C.

IR (mineral oil) 3077, 2646, 1632, 1599, 1529, 1477, 1450, 1396, 1357,1349, 1334, 1317, 1283, 1273, 1252, 1232, 1217, 1205, 1181 cm⁻¹.

EXAMPLE 373

5-Cyano-N- 3-2,2-dimethyl-1-(4a,5,6,7,8,9,10,10a-octahydro-4-hydroxy-2-oxo-2H-cyclooctab!pyran-3-yl)propyl!phenyl!-2-pyridinesulfonamide (Formula DDDD-7,wherein n is 2, R₁ is t-butyl, and R₂ is 5-cyano-2-pyridyl) Refer toChart DDDD

Following the general procedure of Example 370, and making non-criticalvariations, but substituting the title compound of Preparation 159 forthe title compound of Preparation 157, 0.034 g of the title compound isobtained as white crystals.

Physical characteristics are as follows:

MP 182°-185° C.

IR (mineral oil) 3246, 3121, 3098, 2615, 1655, 1633, 1607, 1585, 1575,1491, 1411, 1395, 1354, 1335, 1322, 1311, 1298, 1281, 1275, 1262, 1255,1233, 1206, 1178, 1121, 1109, 1028, 977, 702, 657, 646, 635, 605 cm⁻¹.

HRMS found: 524.2216.

Anal. found: C, 63.86; H, 6.41; N, 7.82.

PREPARATION 160

(3(3R),4S)-3- 2- 1- 3-bis(phenylmethyl)amino!phenyl!-propyl!-5-hydroxy-1,3-dioxo-5-(2-phenylethyl)octyl!-4-phenyl-2-oxazolidinone(Formula W-10 wherein R₁ is 2-phenylethyl) Refer to Chart W

To 100 mL of methylene chloride is added 5.0 g of the title compound ofPreparation 95 (W-8) and the resulting solution cooled to -78° C. underan atmosphere of nitrogen. To that solution is added 1.0 mL of TiCl₄ and1.63 mL of diisopropylethylamine, and the resulting solution is stirredfor 1 hour. Then, 3.30 g of 1-phenyl-3-hexanone is added, and thereaction temperature raised to 0° C. for 2.5 hours. The reaction is thenquenched by the addition of a saturated ammonium chloride solution, andthe mixture is extracted with methylene chloride. The organic extract iswashed with saturated sodium bicarbonate solution and evaporated invacuo to yield 9.7 g of a yellow oil. Column chromatography on 900 gsilica (elution with 10% hexane-methylene chloride, 100% methylenechloride) affords 3.30 g of the title compound as a yellow foam.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.33-7.23, 7.14, 7.04, 6.61-6.50, 5.45, 5.22, 4.71,4.60, 4.48, 4.26, 3.33, 3.15-3.03, 2.58, 2.47-2.31, 1.93, 1.40-1.28,1.24-1.13, 1.11-0.96, 0.88-0.77, 0.62-0.57 ppm.

MP 121°-126° C.

¹³ C NMR (CDCl₃) δ167.2, 167.1, 153.7, 142.6, 141.0, 138.2, 138.1,129.6, 129.5, 129.2, 128.9, 128.8, 128.6, 128.4, 128.3, 127.0, 125.8,125.6, 125.6, 73.1, 70.0, 69.9, 63.9, 57.9, 54.8, 54.7, 51.5, 51.4,48.3, 41.3, 41.0, 40.8, 40.5, 29.8, 29.6, 27.1, 26.9, 16.8, 16.6, 14.6,11.7, 11.6 ppm.

IR (mineral oil) 3525, 3061, 3026, 1777, 1720, 1690, 1601, 1495, 1361,1335, 1238, 1199, 1104, 735, 698 cm⁻¹.

EI-MS: M+!=736.

Anal. found: C, 78.03; H, 7.11; N, 3.79.

PREPARATION 161

(3S)-3- 1-3-Bis(phenylmethyl)amino!phenyl!propyl!-5,6-dihydro-4-hydroxy-6-(2-phenylethyl-6-propyl-pyran-2-one(Formula W-11 wherein R₁ is 2-phenylethyl) Refer to Chart W

To 5 mL of dry tetrahydrofuran is added 2.7 g of the title compound ofPreparation 160 and the resulting solution is cooled to 0° C. under anatmosphere of nitrogen. To that solution is added 0.45 mL of a 1Msolution of potassium t-butoxide in tetrahydrofuran. The reactionmixture is then warmed to 20° C. and stirred for 2 hours. The reactionis quenched with saturated ammonium chloride and extracted with ethylacetate. The organic layer is washed with water, dried and evaporated invacuo to yield 0.28 g of a yellow oil. Column chromatography on 80 g ofsilica gel (elution with 10-30% acetone/hexane) affords 0.195 g of ayellow foam. Crystallization from ethyl acetate/hexane yields 0.146 g ofthe title compound.

Physical characteristics are as follows:

MP 128°-131° C.

¹ H NMR (CDCl₃) δ7.35-7.12, 6.73-6.64, 5.84, 4.73-4.57, 4.12, 2.69-2.61,2.38-2.20, 1.95-1.65, 1.41-1.32, 0.98-0.87 ppm.

¹³ C NMR (CDCl₃) δ204.1, 204.0, 171.7, 171.4, 169.6, 140.9, 140.8,140.6, 140.5, 140.4, 139.9, 139.8, 138.3, 129.7, 129.6, 129.5, 128.9,128.6, 128.5, 128.4, 128.2, 128.1, 127.1, 126.9, 126.8, 126.7, 126.5,126.4, 126.3, 126.2, 126.0, 125.9, 116.8, 112.6, 112.5, 112.4, 112.3,112.2, 112.1, 112.0, 82.0, 81.9, 81.8, 80.4, 80.3, 58.6, 58.5, 54.5,51.4, 50.4, 50.1, 49.9, 47.8, 47.4, 47.0, 46.6, 43.0, 42.9, 42.2, 41.9,40.2, 40.1, 40.0, 39.2, 29.8, 29.7, 29.6, 29.1, 29.0, 26.8, 26.7, 24.7,24.6, 24.3, 16.9, 16.5, 14.0, 12.3 ppm.

IR (mineral oil) 3023, 1637, 1599, 1584, 1575, 1494, 1347, 1300, 1257,1243, 1234, 920, 731, 704, 695 cm⁻¹.

EI-MS: M+!=573.

Anal. found: C, 81.53; H, 7.82; N, 2.34.

a!_(D) (CHCl₃)=-83°

PREPARATION 162

(3S)-3-1-(3-Aminophenyl)propyl!-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-6-propyl-pyran-2-one(Formula W-12 wherein R₁ is 2-phenylethyl) Refer to Chart W

0.63 g of the title compound of Preparation 161 is dissolved in 45 mL ofethyl acetate and 15 mL of methanol. To that solution is added 0.47 g of10% Pd/C, and the resulting mixture is hydrogenated at 50 psi for 2.5hours. The reaction is then filtered through celite and concentrated invacuo to yield 0.466 g of an off-white foam. Column chromatography on 80g of silica gel (elution with 20-50% ethyl acetate-hexane) affords 0.389g of the title compound as an off-white solid.

Physical characteristics are as follows:

MP 155°-159° C.

¹ H NMR (CD₃ OD) δ7.26-7.20, 7.15-7.04, 6.95, 6.81, 6.74, 6.54-6.51,3.98-3.91, 2.68-2.54, 2.25-2.17, 2.02-1.67, 1.43-1.28, 0.99-0.87 ppm.

¹³ C NMR (CD₃ OD) δ171.2, 171.0, 148.5, 148.2, 143.9, 130.4, 130.2,127.8, 120.8, 117.8, 115.3, 107.4, 82.7, 44.6, 44.4, 41.8, 41.7, 41.5,38.4, 31.8, 26.8, 26.7, 18.8, 15.6, 14.3 ppm.

IR (mineral oil) 3085, 3061, 3026, 1617, 1605, 1495, 1314, 1258, 1168,1119, 1065, 1030, 923, 776, 699 cm⁻¹.

EI-MS: M+!=393.

Anal. found: C, 76.13; H, 8.16; N, 3.37.

a!_(D) (MeOH)=-41°

EXAMPLE 374

N- 3- 1-(S)-5,6,-Dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide(Formula W-13 wherein R₁ is 2-phenylethyl) Refer to Chart W

To a solution of 0.200 g of the title compound of Preparation 162 in 5mL of methylene chloride is added 0.12 mL of pyridine. The resultingmixture is cooled to 0° C. and 0.132 g of5-trifluoromethylpyridine-2-sulfonyl chloride is added. The reactionmixture is then stirred at room temperature for 1.5 h, concentrated invacuo, and partitioned between ethyl acetate and water. The organiclayer is concentrated in vacuo to 0.39 g of pink oil. Columnchromatography on 50 g silica gel (elution with 20-50% ethylacetate/hexane) affords 0.252 g of title compound as a white foam.

MP 170°-173° C.

¹ H NMR (CD₃ OD) δ8.95-8.92, 8.23-8.16, 8.04-8.00, 7.25-6.90, 4.86,3.98-3.90, 3.31, 3.30, 2.69-2.46, 2.18-2.09, 1.96-1.65, 1.41-1.28,0.99-0.81 ppm.

¹³ C NMR (CD₃ OD) δ167.3, 147.7, 147.5, 142.9, 142.8, 137.7, 137.0,129.5, 129.2, 126.9, 126.2, 126.1, 124.1, 122.6, 122.5, 120.3, 120.2,81.8, 81.7, 43.6, 43.2, 40.9, 40.5, 37.5, 30.9, 25.8, 25.6, 17.9, 14.7,13.3, 13.2 ppm.

IR (mineral oil) 3087, 3027, 1642, 1606, 1595, 1327, 1260, 1173, 1142,1110, 1074, 1016, 720, 700, 613 cm⁻¹.

FAB-MS: M+H!=603.

Anal. found: C, 61.79; H, 5.86; N, 4.48; S, 5.16.

a!_(D) (MeOH)=-310.

PREPARATION 163

(3S,6R)-3- 1-3-bis(phenylmethyl)amino!phenyl!propyl!-5,6-dihydro-4-hydroxy-6-(2-phenylethyl-6-propyl-pyran-2-one(Formula FFF-2) Refer to Chart FFF

The title compound of Preparation 161 is chromatographed on a 5.1×30 cmCyclobond I 2000 column in an ice bath at 90 mg per injection using anautomated chromatographic system and a mobile phase of acetonitrilecontaining 0.1% diethylamine and 0.05% glacial acetic acid (v/v). Theeluant is monitored at 260 nm, the flow rate is 45 mL/min, andappropriate fractions from multiple injections are combined andconcentrated in vacuo to give 0.300 g of a dark oil. The oil ispartitioned between ethyl acetate, saturated aqueous sodium bicarbonatesolution, and water. The organic layer is separated and concentrated invacuo. Column chromatography on 50 g of silica gel (elution with 10-20%acetone/hexane) affords 0.22 g of the title compound of the compound asa colorless oil.

Physical characteristics are as follows:

The retention time of the title compound is 57 min.

PREPARATION 164

(3S,6S)-3- 1-3-bis(phenylmethyl)amino!phenyl!propyl!-5,6-dihydro-4-hydroxy-6-(2-phenylethyl-6-propyl-pyran-2-one(Formula FFF-3) Refer to Chart FFF

The title compound of Preparation 161 is separated as described inPreparation 163 above. Further purification as described in Preparation163 affords 0.117 g of the title compound as a colorless oil.

Physical characteristics are as follows:

The retention time of the title compound is 66 min.

PREPARATION 165

(3S,6R)-3-1-(3-aminophenyl)propyl!-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-6-propyl-pyran-2-one(Formula FFF-4) Refer to Chart FFF

Following the general procedure of Preparation 162, and makingnon-critical variations, but substituting the title product ofPreparation 163 for the title product of Preparation 161, 0.022 g of thetitle compound is obtained.

Physical characteristics are as follows:

¹ H NMR (CD₃ OD) δ7.25-7.18, 7.15-7.12, 7.07-7.05, 6.97, 6.82-,6.76-6.71, 6.53, 4.00-3.92, 2.67-2.54, 2.29-2.15, 2.06-1.92, 1.90-1.62,1.46-1.28, 0.97-0.88 ppm.

EXAMPLE 375

(3S,6R)-N- 3- 1-5,6,-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide(Formula FFF-5) Refer to Chart FFF

Following the general procedure of Example 374, and making non-criticalvariations, but substituting the title product of Preparation 165 forthe title product of Preparation 162, 0.024 g of the title compound isobtained as a white foam.

Physical characteristics are as follows:

MP 156°-159° C.

¹ H NMR (CD₃ OD) δ8.90, 8.20-8.17, 8.02-7.99, 7.28-6.88, 4.00-3.90,2.71-2.46, 2.20-2.10, 1.98-1.67, 1.41-1.28, 0.98-0.81 ppm.

EXAMPLE 376

(3S)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide(Formula W-13) Refer to Chart W

The title compound of Preparation 99 (formula W-12) 182 mg is dissolvedin 5 mL of methylene chloride and 133 μL of pyridine added. The reactionis cooled to 0° C. and 142 mg of5-trifluoromethyl-2-pyridinesulfonylchloride added. The reaction isstirred for 30 minutes and the methylene chloride is evaporated and theresulting material diluted with ethyl acetate. The organic solution iswashed with water, brine and then dried over sodium sulfate. Evaporationof solvent gives 580 mg of crude product. Silica gel chromatography (50g) eluting with 50% ethyl acetate/hexane affords 211 mg of the desiredproduct as a white foam.

Physical characteristics are as follows:

Anal. found: C, 57.80; H, 5.95; N, 5.01; S, 5.64

α!_(D) (18.094 mg/2 mL CHCl₃)=-30°

EXAMPLE 377

(3R)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide(Formula X-13) Refer to Chart X

The title compound of Preparation 107 (formula X-12) 170 mg is dissolvedin 5 mL of methylene chloride and 136 μL of pyridine added. The reactionis cooled to 0° C. and 132 mg of5-trifluoromethyl-2-pyridinesulfonylchloride is added. The reaction isstirred for 30 minutes and the methylene chloride is evaporated and theresulting material diluted with ethyl acetate. The organic solution iswashed with water, brine and then dried over sodium sulfate. Evaporationof solvent gives crude product which is chromatographed over 50 g ofsilica gel eluting with 50% ethyl acetate/hexane affords 225 mg of thedesired product as a white foam.

Physical characteristics are as follows:

α!_(D) (mg/2 mL CHCl₃)=+29°

PREPARATION 166

(3S)(4R) 3- 2- 1- 3-Bis(phenylmethyl)amino!phenyl!-propyl!-5-hydroxy-1,3-dioxo-5-phenethyloctyl!-4-phenyl-2-oxazolidinone(Formula X-10 where R₁ is phenethyl) Refer to Chart X

To 1.12 g of the title compound of Preparation 104 is added 20 mL ofmethylene chloride and the resulting solution cooled to -78° C. To thatsolution is added 237 μL of TiCl₄ followed by 400 μL ofdiisopropylethylamine and the resulting solution is stirred at -78° C.for 1 hour. To the aforementioned solution is added 776 μL of1-phenyl-3-hexanone and stirring continued at -40° C. for 40 minutes andthen the temperature is raised to -10° C. for 1.5 hours. The reaction isquenched with the addition of a saturated ammonium chloride solution,then extraction with methylene chloride and evaporation of the organicextracts. The crude material is chromatographed over 200 g of silica geleluting with 10% hexane/methylene chloride to afford 870 mg of the titlecompound.

Physical characteristics are as follows:

IR (mineral oil) 2956, 2926, 2854, 1777, 1600, 1494, 1452, 698 cm⁻ 1.

α!_(D) (16.578 mg in CHCl₃)=+4°

Mass Spectrum: molecular ion at 736.

Anal. found. C, 78.00; H, 7.14; N, 3.61.

PREPARATION 167

(3R) 3- 1- 3-Bis(phenylmethyl)amino!phenyl!propyl!-5,6-dihydro-4-hydroxy-6-phenethyl-6-propyl-2H-pyran-2-one(Formula X-11 where R₁ is phenethyl) Refer to Chart X

The compound of Preparation 166 (750 mg) is added to 5 mL of dry THF andpotassium tert. butoxide (1.0M in THF; 1.2 mL) is added. The reaction isstirred at 20° C. for 30 minutes and then quenched by the addition of asaturated ammonium chloride solution. The reaction is extracted withethyl acetate, the organic extracts washed with water and brine andfinally evaporated to afford the crude product. Silica gelchromatography over 100 g of silica gel eluting with 15% ethylacetate/hexane affords 511 mg of the title product.

Physical characteristics are as follows:

IR (mineral oil) 2956, 2855, 1628, 1599, 1577, 1494, 1385, 1364, 697 cm⁻1.

Anal. found: C, 81.30; H, 7.68; N, 2.30

Mass spectrum: molecular ion at 573.

α!_(D) (18.116 mg/2 mL CH₃ OH)=+38°

PREPARATION 168

(3R) 3- 1-3-aminophenyl!propyl!-5,6-dihydro-4-hydroxy-6-phenethyl-6-propyl-2H-pyran-2-one(Formula X-12 where R₁ is phenethyl) Refer to Chart X

The compound of Preparation 167 (370 mg) is dissolved in 35 mL of ethylacetate and 6 ml of methanol. To that solution is added 200 mg of 10% Pdon Carbon catalyst and the reaction is hydrogenated under 50 psi ofhydrogen for 2 hours. The reaction is evaporated and chromatographedover 60 g of silica gel to yield 244 mg of the title compound.

Physical characteristics are as follows:

IR (mineral oil) 3025, 2954, 2871, 2854, 1635, 1619, 1604, 1494, 1456,1383, 1378, 1256 cm⁻ 1.

α!_(D) (16.764 mg/mL in CH₃ OH)=+39°.

Mass spectrum: molecular ion at 393.

Anal. found: C, 75.79; H, 8.05; N, 3.27.

EXAMPLE 378

(3R)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide(Formula X-13 where R₁ is phenethyl) Refer to Chart X

The product of Preparation 168 (156 mg) is added to 5 mL of methylenechloride. To that solution is added 96 μL of pyridine and then thereaction is cooled to 0° C. To the aforementioned solution is added 102mg of 5-trifluoromethyl-2-pyridinyl sulfonyl chloride. The reaction isstirred for 1 hour and then poured into ethyl acetate, washed withwater, brine and dried with MgSO₄. The solvent is evaporated in vacuoand the resulting material chromatographed over 100 g of silica geleluting with 50% ethyl acetate/hexane to yield 200 mg of the titlecompound.

Physical characteristics are as follows:

Mass spectrum: molecular ion at 602.

IR (mineral oil) 2953, 2922, 2870, 2853, 1642, 1605, 1459, 1457, 1326,1259, 1180, 1171, 1141 cm⁻ 1.

UV (EtOH) λ_(max) (ε) 216 (22300), 264 sh (10700), 270 (11500), 279(12100)

Anal. found: C, 57.53; H, 5.98; N, 4.84.

EXAMPLE 379

(3R,6S)-N- 3- 1-(56-Dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide(Formula X-13 where R₁ is phenethyl) Refer to Chart X

The product of Example 378 is added to isopropanol and injected onto a0.46×25 cm Cyclobond I 2000 column (Advanced Separations Technoloyies,Inc., Whippany, N.J.). The column is in an ice-water bath. The sample iseluted at 1.0 mL/min. with acetonitrile containing 0.1% diethylamine and0.6% glacial acetic acid (V/V). The monitor is set at 250 nm. Theearlier eluting diastereomer is identical to the compound of Example298. The second eluting diastereomer is purified over 60 g of silica geleluting with 40% ethyl acetate/hexane to afford 13 mg of the titlecompound.

Physical characteristics are as follows:

Opposite stereochemistry at C-6 to the compound of Example 298.

¹ H-NMR (CD₃ OD, δ) 8.91, 8.19, 8.16, 8.02, 7.99, 7.25, 7.18, 7.15,7.13, 7.11, 7.04, 6.97, 6.89, 6.75, 3.95,2.69, 2.64, 2.53, 2.48, 2.13,1.91, 1.71, 1.68, 1.37, 1.19, 1.17, 1.14, 0.94, 0.92, 0.89, 0.85, 0.83,0.80, 0.93.

PREPARATION 169

(3S)-3- (3-Bis(phenylmethyl)amino)phenyl!-4,4-dimethylpentanoic acidmethyl ester (Formula LLL-9) Refer to Chart LLL

To anhydrous methanol (2 mL) at room temperature is added titanium (IV)chloride (0.07 mL). The resulting light green solution is stirred for 2h, treated with the compound of formula LLL-2 wherein R is phenyl (100mg), prepared by procedures analogous to those described in Chart FF,and refluxed for 18 h. The reaction mixture is allowed to cool and ispartitioned between 1N HCl and diethyl ether. The organic layer isseparated washed with brine, dried over anhydrous sodium sulfate, andconcentrated in vacuo. Purification by flash chromatography eluting withhexane/ethyl acetate (95:5) affords the title compound (58 mg) as alight amber oil.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.32-7.20, 7.04, 6.61-6.48, 4.61, 3.48, 2.85-2.80,2.72-2.55, 0.75 ppm

¹³ C NMR (CDCl₃) δ173.69, 148.45, 142.51, 138.91, 128.53, 128.17,126.78, 117.98, 114.49, 110.89, 54.54, 52.24, 51.40, 35.56, 33.65, 27.87ppm

MS (EI) m/z 415.

PREPARATION 170

(3S)-3- (3-Bis(phenylmethyl)amino)phenyl!-4,4-dimethylpentanoic acid(Formula LLL-10) Refer to Chart LLL

The compound of formula LLL-9 (406 mg) of Preparation 169 is slurried inglacial acetic acid (2.6 mL) and 6N sulfuric acid. The reaction mixtureis refluxed for 5 h, allowed to cool and is partitioned between waterand diethyl ether. The aqueous layer is separated and extracted two moretimes with diethyl ether. The combined organic layers are washed withbrine, dried over anhydrous sodium sulfate, and concentrated in vacuo.The resulting light brown residue is dissolved in diethyl ether andtreated with dicyclohexylamine (0.16 mL) at 0° C. The solids areisolated, washed with diethyl ether and dried in vacuo. The light brownsolid is suspended in diethyl ether and washed with 0.25N HCl. Theorganic layer is washed with brine, dried over anhydrous sodium sulfate,and concentrated in vacuo, affording the title product (54 mg) as alight brown amorphous solid.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.31-7.19, 7.04, 6.61-6.48, 4.61, 2.81-2.56, 0.74 ppm

¹³ C NMR (CDCl₃) δ179.15, 148.56, 142.28, 138.83, 128.55, 128.23,126.76, 117.90, 114.49, 110.98, 54.51, 51.83, 35.45, 33.67, 27.84 ppm

MS (EI) m/z 401.

PREPARATION 171

N- (S)-4-Benzyl-2-oxazolidinone!3-aminocinnamate amide (Formula HHH-4)Refer to Chart HHH

A 1 liter round-bottomed flask with nitrogen inlet and addition funnelis charged with 10.02 g of commercially available(S)-4-benzyl-2-oxazolidinone and 260 mL of tetrahydrofuran and thencooled to -78° C. To the aforementioned solution is added 37 mL ofn-butyl lithium during which time a white solid separates from thereaction solution. To that suspension is added 11.46 g oftrans-3-nitrocinnamic acid chloride (prepared from the treatment ofcommercially available 3-nitrocinnamic acid with oxalyl chloride) in asmall volume of THF. The resulting pale yellow homogeneous solution isallowed to warm to room temperature and quenched with a saturatedammonium chloride solution and is extracted with ethyl acetate. Theorganic layer is separated, washed with brine and water, dried overmagnesium sulfate, filtered and concentrated to give a reddish brownsyrup (formula HHH-3 in Chart HHH) which is used without furtherpurification. The aforementioned crude reaction mixture is added toethanol containing 64.18 grams of SnCl₂.2H₂ O and that mixture heated atreflux for 20 minutes. The reaction is cooled to room temperature andpoured into ice. The mixture is brought to pH 9-10 with saturatedaqueous Na₂ CO₃. The mixture is filtered and the filter cake washedextensively with ethyl acetate. The filtrate is washed with brine andthe organic phase is dried (Na₂ SO₄), filtered, and concentrated invacuo to give a yellow solid. Recrystallization from ethanol gives 11.56g of the title product.

Physical characteristics are as follows:

IR (mineral oil) 3450, 3369, 2924, 1771, 1678, 1620, 1462, 1392, 1357,1347, 1214 cm⁻ 1

α!_(D) (14.418 mg/mL in CHCl₃)=+51°

PREPARATION 172

N- (S)-4-Benzyl-2-oxazolidinone!3-(bis(phenylmethyl)amino) cinnamateamide (Formula HHH-5) Refer to Chart HHH

The amine of formula HHH-4 from Preparation 172 (10.13 g), 10.48 g ofpotassium carbonate, 8.3 mL of benzyl bromide and 100 mL of acetonitrileis heated at reflux for 3 hours. The reaction is cooled to roomtemperature and partitioned between water and ethyl acetate. The aqueousis extracted several additional times with ethyl acetate. The combinedethyl acetate extracts are dried (Na₂ SO₄), filtered and concentrated invacuo. The residue is purified via silica gel chromatography elutingwith 25% ethyl acetate/hexane to yield 8.87 g of the title product.

Physical characteristics are as follows:

¹³ C-NMR (CDCl₃, ppm) 165, 153, 149, 147, 138, 135, 129.6, 129.3 128.8,128.6, 127, 126.9, 126.5, 116.54, 116.50, 114, 113, 65, 55, 54, 37

IR (mineral oil) 2954, 2870, 2854, 1776, 1677, 1616, 1595, 1493, 1454,1353, 1209, 988 cm⁻ 1

PREPARATION 173

(3S)(4S) 3- 3-(3-(bis(phenylmethyl)aminophenyl)pentanoyl!-4-phenyl-2-oxazolidinone (Formula HHH-6) Refer to Chart W

A 100-mL, three-necked flask equipped with a stir-bar, 25-mLpressure-equalizing addition funnel, and a nitrogen inlet is chargedwith copper(I) bromide dimethyl sulfide complex (1.69 g), 20 mL oftetrahydrofuran and 10 mL of dimethyl sulfide. The addition funnel ischarged with the title compound of Preparation 172 (2.747 g) and 10 mLof tetrahydrofuran. The reaction mixture is cooled to -40° C. and ethylmagnesium bromide (5.5 mL of a 3.0M solution in ether) is added dropwiseover 5 min. The resulting black mixture is stirred another 10 min at-40° C. and then allowed to warm to -10° C. The solution of the titlecompound of Preparation 172 in tetrahydrofuran is added dropwise to thereaction mixture over 17 min. The addition funnel is then rinsed withanother 3 mL of tetrahydrofuran, and the reaction mixture is stirred for2.5 h at ca. -40° to -60° C. The reaction is quenched by pouring themixture into 50 mL of saturated aqueous ammonium chloride solution, andthe organic solvents are removed by concentration in vacuo. Theresulting residue is partitioned between 75 mL of ethyl acetate and 50mL of water and filtered through glass wool. The organic layer is thenseparated, washed with two 100-mL portions of 10% ammonium hydroxidesolution and 50 mL of brine, dried over magnesium sulfate, filtered andconcentration in vacuo to yield 3.59 g of a yellow oil. Columnchromatography on 150 g of silica gel (elution with 5-15% ethylacetate/hexane) affords two diastereomeric products. 1.602 g of thetitle compound (the less polar diastereomer) is isolated as a paleyellow oil

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.32-7.17, 7.06, 6.60, 6.55, 4.63, 4.43-4.37, 4.00,3.85, 3.37, 3.20, 3.08, 3.02-2.92, 2.62, 1.71-1.48, 0.73 ppm!

Also isolated from the column is 0.310 g of the more polar diastereomeras a pale yellow oil.

Physical characteristics are as follows:

¹ H NMR (CDCl₃) δ7.32-7.18, 7.12, 7.05, 6.64-6.56, 4.63, 4.60-4.52,4.08-4.04, 3.48-3.38, 3.07-2.96, 2.48, 1.69-1.48, 0.73 ppm.

In addition, fractions containing 0.708 g of a ca. 1:4 ratio mixture ofthe less polar to more polar diastereomers are collected from thecolumn.

PREPARATION 174

(3S,6S)-3-1-(3-aminophenyl)propyl!-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-6-propyl-2H-pyran-2-one(Formula FFF-6) Refer to Chart FFF

Following the general procedure of Preparation 162, and makingnon-critical variations, but substituting the title product ofPreparation U-141164! for the title product of Preparation 161, 0.040 gof crude title compound is obtained. This compound is used immediatelyin the next step without further purification.

EXAMPLE 380

(3S,6S)-N- 3- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide(Formula FFF-7) Refer to Chart FFF

Following the general procedure of Example 374, and making non-criticalvariations, but substituting the title product of Preparation 174 forthe title product of Preparation 162, 0.015 g of the title compound isobtained as a white foam.

Physical characteristics are as follows:

¹ H NMR (CD₃ OD) δ8.95, 8.25-8.21, 8.07-8.02, 7.25-6.93, 3.94-3.88,2.70-2.51, 2.20-2.18, 1.97-1.66, 1.40-1.30, 0.92-0.81 ppm.

Thus, for example, the compounds of the present invention include thefollowing individual stereoisomers:

5-cyano-N- 3-(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

5-cyano-N- 3-(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(S)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

5-cyano-N- 3-(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(S)-(3,3,2-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

5-cyano-N- 3-(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

N- 3-(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(R)-(2-phenethyl)-6-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N- 3-(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(S)-(2-phenethyl)-6-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N- 3-(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(S)-(2-phenethyl)-6-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N- 3-(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(R)-(2-phenethyl)-6-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

5-amino-N- 3-(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

5-amino-N- 3-(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(S)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

5-amino-N- 3-(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

5-amino-N- 3-(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(S)-(3,3,3-trifluoropropyl)-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

N- 3-(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R)-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

N- 3-(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(S)-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

N- 3-(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R)-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

N- 3-(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(S)-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3-(R)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3-(S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,

4-Trifluoromethyl-N- 3-(R)- -4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,

4-Trifluoromethyl-N- 3-(S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3-(R)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!1-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3-(S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!1-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3-(R)- 1-4-hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3-(S)- 1-4-hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,

4-Trifluoromethyl-N- 3-(R)- 1-4-hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,

4-Trifluoromethyl-N- 3-(S)- 1-4-hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,

4-Trifluoromethyl-N- 3-(R)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide,

4-Trifluoromethyl-N- 3-(S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6(R)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6(R)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide,

4-Trifluoromethyl-N- 3(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6(R)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide,

4-Trifluoromethyl-N- 3(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide,

4-Trifluoromethyl-N- 3(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6(R)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide,

4-Trifluoromethyl-N- 3(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)-n-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6(R)-n-propyl-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)-n-propyl-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6(R)-n-propyl-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,

5-Trifluoromethyl-N- 3(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)-n-propyl-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide,

5-Cyano-N- 3(R)-(1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Cyano-N- 3(R)-(1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Cyano-N- 3(S)-(1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Cyano-N- 3(S)-(1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

N- 3(R)- 1-(5,6-Dihydro-4-hydroxy-2-oxo-6(R)-2-phenylethyl!-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N- 3(R)- 1-(5,6-Dihydro-4-hydroxy-2-oxo-6(S)-2-phenylethyl!-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N- 3(S)- 1-(5,6-Dihydro-4-hydroxy-2-oxo-6(R)-2-phenylethyl!-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N- 3(S)- 1-(5,6-Dihydro-4-hydroxy-2-oxo-6(S)-2-phenylethyl!-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl!phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

5-Amino-N- 3(R)-(1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(S)-(1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(S)-(1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(R)-(1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(R)-(1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(R)-(1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(S)-(1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(S)-(1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(R)-(1- 6(R)-(2-4-fluorophenyl!ethyl)-5,6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(R)-(1- 6(S)-(2-4-fluorophenyl!ethyl)-5,6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(S)-(1- 6(R)-(2-4-fluorophenyl!ethyl)-5,6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(S)-(1- 6(S)-(2-4-fluorophenyl!ethyl)-5,6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

N- 3(R)-(1-5,6-Dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N- 3(S)-(1-5,6-Dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

5-Amino-N- 3(R)-(1-5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Amino-N- 3(S)-(1-5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Cyano-N- 3(R)-(1-5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

5-Cyano-N- 3(S)-(1-5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl!-2,2-dimethylpropyl)phenyl!-2-pyridinesulfonamide,

N- 3(R)-(1-6,6-Bis(2-phenylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!propyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N- 3(S)-(1-6,6-Bis(2-phenylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!propyl)phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N- 3(R)-(1-6,6-Bis(2-phenyl-ethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!propyl)phenyl!-5-cyano-2-pyridinesulfonamide,

N- 3(S)-(1-6,6-Bis(2-phenyl-ethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!propyl)phenyl!-5-cyano-2-pyridinesulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-aminopyridine-2-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-aminopyridine-2-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)-2,2-dimethylpropyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-propyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-propyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-propyl}phenyl!-5-aminopyridine-2-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-propyl}phenyl!-5-aminopyridine-2-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-1-methyl-1H-imidazole-4-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-aminopyridine-2-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-aminopyridine-2-sulfonamide,

N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-aminopyridine-2-sulfonamide,

N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-fluorophenyl)ethyl)-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-aminopyridine-2-sulfonamide,##STR2##

                  TABLE I                                                         ______________________________________                                        Compound of                                                                              HIV Protease FITC Assay                                            Example No.                                                                              Dose (uM)  Protease % Inhib                                                                          K.sub.i (nM)                                ______________________________________                                        136        0.123      71.65                                                              0.370      85.67                                                              1.100      99.02                                                              3.300      100.99                                                             10.000     102.37                                                             30.000     101.94                                                                                    1.320                                         145A     0.123      108.66                                                             0.370      111.34                                                             1.100      118.54                                                             3.300      115.43                                                             10.000     113.05                                                             30.000     114.19                                                                                    1.100                                       137        0.123      98.83                                                              0.370      91.54                                                              1.100      100.7                                                              3.300      109.9                                                              10.000     98.17                                                              30.000     93.82                                                                                     0.520                                                                         0.700                                       138        0.123      100.88                                                             0.370      95.51                                                              1.100      101.11                                                             3.300      99.64                                                              10.000     94.75                                                              30.000     104.68                                                                                    0.730                                                                         1.400                                        97        0.123      104.87                                                             0.370      106.06                                                             1.100      110.44                                                             3.300      106.67                                                             10.000     115.76                                                             30.000     115.47                                                                                    1.000                                        98                               0.740                                       First Compound                                                                                                  0.800                                        98                               0.840                                       Second Compound                                                                                                 0.800                                       139        0.123      98.33                                                              0.370      101.22                                                             1.100      104.71                                                             3.300      99.3                                                               10.000     99.28                                                              30.000     102.85                                                                                    1.890                                       140        0.123      103.22                                                             0.370      96.01                                                              1.100      107.37                                                             3.800      112.51                                                             10.000     112.53                                                             30.000     119.14                                                                                    1.440                                        40        0.123      59.6                                                               0.370      101.71                                                             1.100      98.73                                                              3.300      105.16                                                             10.000     88.7                                                               30.000     72.74                                                                                     10.800                                       41        0.123      103                                                                0.370      102.38                                                             1.100      103.92                                                             3.300      100.93                                                             10.000     85.88                                                              30.000     72.79                                                                                     3.170                                        44        0.123      98.43                                                              0.370      114.5                                                              1.100      119.79                                                             3.300      112.7                                                              10.000     101.66                                                             30.000     80.02                                                                                     1.800                                         145B     0.123      81.81                                                              0.370      88.38                                                              1.100      96.54                                                              3.300      87.85                                                              10.000     102.12                                                             30.000     84.52                                                                                     1.240                                       135        0.123      33.21                                                              0.370      84.5                                                               1.100      99.09                                                              3.300      96.86                                                              10.000     101.49                                                             30.000     102.4                                                                                     0.480                                       104        0.123      <10                                                                0.370      61.68                                                              1.100      81.78                                                              3.300      93.28                                                              10.000     96.4                                                               30.000     109.22                                                                                    1.600                                        48        0.123      111.37                                                             0.370      103.64                                                             1.100      110.44                                                             3.300      89.27                                                              10.000     110.97                                                             30.000     105.44                                                                                    0.520                                        49        0.123      111.16                                                             0.370      119.71                                                             1.100      120.17                                                             3.300      106.02                                                             10.000     108.34                                                             30.000     112.5                                                                                     0.960                                        50        0.123      100.54                                                             0.370      108.31                                                             1.100      112.66                                                             3.300      112.42                                                             10.000     101.02                                                             30.000     84.79                                                                                     1.780                                       105        0.123      101.26                                                             0.370      114.56                                                             1.100      107.19                                                             3.300      110.88                                                             10.000     111.16                                                             30.000     110.6                                                                                     0.880                                        52        0.123      85.08                                                              0.370      87.32                                                              1.100      92.64                                                              3.300      97.38                                                              10.000     97.15                                                              30.000     88.89                                                                                     1.400                                        53        0.123      88.61                                                              0.370      97.74                                                              1.100      97.95                                                              3.300      99.62                                                              10.000     90.16                                                              30.000     84.37                                                                                     0.900                                        55        0.123      <10                                                                0.370      18.77                                                              1.100      58.27                                                              3.300      86.98                                                              10.000     98.33                                                              30.000     85.88                                                                                     1.700                                       107        0.123      92.69                                                              0.370      99.24                                                              1.100      105.15                                                             3.300      103.44                                                             10.000     110.33                                                             30.000     103.47                                                                                    0.890                                                                         0.700                                        99        0.123      85.69                                                              0.370      101.55                                                             1.100      108.05                                                             3.300      100.05                                                             10.000     106.61                                                             30.000     103.12                                                                                    0.660                                       141        0.123      78.72                                                              0.370      88.65                                                              1.100      92.04                                                              3.300      88.26                                                              10.000     97.8                                                               30.000     98.48                                                                                     1.400                                       142        0.123      78.01                                                              0.370      92.52                                                              1.100      106.64                                                             3.300      105.15                                                             10.000     110.58                                                             30.000     106.77                                                                                    1.600                                        56        0.123      104.11                                                             0.370      108.31                                                             1.100      105.31                                                             3.300      105.47                                                             10.000     114.94                                                             30.000     111.25                                                                                    0.230                                        57        0.123      99.07                                                              0.370      105.17                                                             1.100      110.68                                                             3.300      97.8                                                               10.000     104.74                                                             30.000     115.02                                                                                    0.360                                        58        0.123      64.87                                                              0.370      83.71                                                              1.100      94.24                                                              3.300      95.88                                                              10.000     100.27                                                             30.000     89.81                                                                                     3.800                                        59        0.123      76.69                                                              0.370      90.54                                                              1.100      101.9                                                              8.300      99.87                                                              10.000     105.16                                                             30.000     102.02                                                                                    3.500                                        60        0.123      73.03                                                              0.370      94.3                                                               1.100      101.28                                                             3.300      100.84                                                             10.000     105.68                                                             30.000     107.38                                                                                    0.950                                        61        0.123      86.83                                                              0.370      95.51                                                              1.100      103.35                                                             3.300      102.54                                                             10.000     105.61                                                             30.000     103.53                                                                                    0.710                                         93A      0.123      59.48                                                              0.370      90.42                                                              1.100      103.54                                                             3.300      108.54                                                             10.000     109.19                                                             30.000     96.57                                                                                     6.060                                       143        0.123      80.78                                                              0.370      97.65                                                              1.100      104.91                                                             3.300      102.39                                                             10.000     101.25                                                             30.000     103.08                                                                                    0.800                                       144        0.123      80.58                                                              0.370      87.39                                                              1.100      93.82                                                              3.300      100.01                                                             10.000     98.12                                                              30.000     95.88                                                                                     1.200                                       145        0.123      73.63                                                              0.370      89.78                                                              1.100      99.69                                                              3.300      94.8                                                               10.000     96.85                                                              30.000     87.97                                                                                     0.490                                       100        0.123      102.53                                                             0.370      100.67                                                             1.100      91.01                                                              3.300      96.54                                                              100.000    100.86                                                             30.000     100.62                                                                                    0.730                                        62        0.123      76.18                                                              0.370      85.15                                                              1.100      85.28                                                              3.300      78.67                                                              10.000     79.69                                                              30.000     79.39                                                                                     0.800                                       108        0.123      103.43                                                             0.370      102.13                                                             1.100      101.87                                                             3.300      102.41                                                             10.000     107.73                                                             30.000     106.39                                                                                    0.160                                       109        0.123      105.42                                                             0.370      99.35                                                              1.100      103.75                                                             3.300      100.96                                                             10.000     108.56                                                             30.000     109.31                                                  239        0.123      83.64                                                              0.370      96.63                                                              1.100      98.41                                                              3.300      99.53                                                              10.000     103.21                                                             30.000     108.02                                                                                    1.440                                                                         0.860                                       152        0.123      11.52                                                              0.370      80.2                                                               1.100      95.79                                                              3.300      94.43                                                              10.000     95.45                                                              30.000     96.47                                                                                     0.710                                        8         0.123      99.23                                                              0.370      110.11                                                             1.100      102.93                                                             3.300      110.02                                                             10.000     105.11                                                             30.000     101.91                                                                                    0.350                                        9         0.123      99.09                                                              0.370      103.78                                                             1.100      104.9                                                              3.300      104.69                                                             10.000     107.08                                                             30.000     107.87                                                                                    0.420                                        10        0.123      102.17                                                             0.370      111.74                                                             1.100      115.65                                                             3.300      119.47                                                             10.000     128.59                                                             30.000     130.05                                                                                    5.710                                       151        0.123      111.03                                                             0.370      114.59                                                             1.100      117.62                                                             3.300      118.9                                                              10.000     116.34                                                             30.000     114.87                                                                                    0.360                                       153        0.123      81.27                                                              0.370      91.11                                                              1.100      100.49                                                             3.300      104.76                                                             10.000     102.76                                                             30.000     100.71                                                                                    1.850                                       154        0.123      99.8                                                               0.370      98.17                                                              1.100      99.52                                                              3.300      97.59                                                              10.000     103.54                                                             30.000     99.18                                                                                     0.220                                       240        0.123      96.32                                                              0.370      100.98                                                             1.100      102.71                                                             3.300      101.88                                                             10.000     104.28                                                             30.000     107.17                                                                                    1.300                                        1         0.123      75.4                                                               0.370      87.3                                                               1.100      97.1                                                               3.300      96.76                                                              10.000     99.68                                                              30.000     97.43                                                                                     15.000                                      101        0.123      70.24                                                              0.370      83.98                                                              1.100      93.35                                                              3.300      97.01                                                              10.000     102.48                                                             30.000     97.35                                                                                     0.660                                       146        0.123      68.12                                                              0.370      87.38                                                              1.100      103.18                                                             3.300      103.26                                                             10.000     102.54                                                             30.000     101.95                                                                                    0.690                                       147        0.123      77.45                                                              0.370      102.86                                                             1.100      111.6                                                              3.300      110.34                                                             10.000     114.04                                                             30.000     108.28                                                                                    1.000                                       110        0.123      77.89                                                              0.370      82.72                                                              1.100      95.11                                                              3.300      99.1                                                               10.000     99.22                                                              30.000     101.27                                                                                    3.260                                                                         3.630                                       102        0.123      87.11                                                              0.370      92.73                                                              1.100      102.21                                                             3.300      110.44                                                             10.000     116.72                                                             30.000     107.83                                                                                    0.700                                       103        0.123      65.51                                                              0.370      82.58                                                              1.100      96.86                                                              3.300      100.29                                                             10.000     104.76                                                             30.000     96.05                                                                                     1.720                                       194        0.123      <10                                                                0.370      20.03                                                              1.100      53.89                                                              3.300      75.23                                                              10.000     85.48                                                              30.000     85.18                                                   195        0.123      60.89                                                              0.370      85.08                                                              1.100      90.79                                                              3.300      90.83                                                              10.000     93.14                                                              30.000     92.69                                                                                     3.700                                       150        0.123      78.42                                                              0.370      96.45                                                              1.100      100.07                                                             3.300      102.81                                                             10.000     106.88                                                             30.000     109.34                                                                                    5.900                                       148        0.123      81.35                                                              0.370      91.68                                                              1.100      95.57                                                              3.300      90.04                                                              10.000     99.17                                                              30.000     93.52                                                                                     4.770                                                                         18.100                                      149        0.123      80.51                                                              0.370      87.52                                                              1.100      96.32                                                              3.300      92.86                                                              10.000     97.12                                                              30.000     95.99                                                                                     3.410                                                                         62.700                                       94        0.123      75.76                                                              0.370      106.6                                                              1.100      107.3                                                              3.300      104.91                                                             10.000     109.2                                                              30.000     111.29                                                                                    16.370                                       95        0.123      91.2                                                               0.370      102.33                                                             1.100      105.86                                                             3.300      112.79                                                             10.000     110.04                                                             30.000     112.69                                                                                    5.350                                        96        0.123      94.17                                                              0.370      119.36                                                             1.100      122.12                                                             3.300      111                                                                10.000     111.32                                                             30.000     109.23                                                                                    5.300                                        42        0.123      86.15                                                              0.370      102.71                                                             1.100      98.26                                                              3.300      102.4                                                              10.000     91.43                                                              30.000     76.12                                                                                     3.100                                        43        0.123      85.63                                                              0.370      99.01                                                              1.100      95.68                                                              3.300      96.68                                                              10.000     101.58                                                             30.000     85.57                                                                                     3.650                                        45        0.123      82.22                                                              0.370      94.37                                                              1.100      101.04                                                             3.300      103.16                                                             10.000     89.76                                                              30.000     67.5                                                                                      4.780                                        46        0.123      85.86                                                              0.370      99.19                                                              1.100      103.31                                                             3.300      97.62                                                              10.000     91.45                                                              30.000     74.13                                                                                     2.920                                        47        0.123      66.3                                                               0.370      86.79                                                              1.100      94.7                                                               3.300      100.95                                                             10.000     98.68                                                              30.000     84.45                                                                                     3.000                                                                         2.980                                        51        0.123      98.71                                                              0.370      103.68                                                             1.100      104.78                                                             3.300      101.27                                                             10.000     95.07                                                              30.000     79.72                                                                                     2.660                                       106        0.123      60.94                                                              0.370      86.56                                                              1.100      93.7                                                               3.300      98.88                                                              10.000     99.03                                                              30.000     106.06                                                                                    3.290                                        54        0.123      46.64                                                              0.370      72.41                                                              1.100      87.91                                                              3.300      89.11                                                              10.000     87.77                                                              30.000     91.99                                                                                     13.300                                      146        10.000     102.54                                                             30.000     101.95                                                                                    0.690                                       192        0.123      44.04                                                              0.370      76.28                                                              1.100      93.96                                                              3.300      96.93                                                              10.000     103.33                                                             30.000     94.38                                                                                     7.200                                       193        0.123      18.42                                                              0.370      40.3                                                               1.100      77.74                                                              3.300      98.1                                                               10.000     108.41                                                             30.000     103.17                                                                                    35.000                                       11        0.123      78.93                                                              0.370      95.26                                                              1.100      100.26                                                             3.300      95.12                                                              10.000     99.66                                                              30.000     104.39                                                                                    1.900                                        12        0.123      75.65                                                              0.370      87.16                                                              1.100      91.79                                                              3.300      91.11                                                              10.000     94.74                                                              30.000     95.69                                                                                     2.150                                        13        0.123      68.94                                                              0.370      88.07                                                              1.100      93.98                                                              3.300      95.51                                                              10.000     98.61                                                              30.000     104.2                                                                                     4.150                                        14        0.123      65.67                                                              0.370      87.96                                                              1.100      96.79                                                              3.300      96.56                                                              10.000     101.77                                                             30.000     106.39                                                                                    6.880                                        15        0.123      77.63                                                              0.370      88.45                                                              1.100      92.44                                                              3.300      94.03                                                              10.000     95.84                                                              30.000     99.23                                                                                     2.800                                        63        0.123      68.88                                                              0.370      79.56                                                              1.100      88.58                                                              3.300      87.44                                                              10.000     83.58                                                              30.000     78.84                                                    64        0.123      27.95                                                              0.370      50.83                                                              1.100      75.60                                                              3.300      80.88                                                              10.000     82.03                                                              30.000     84.39                                                   250                               1.2                                         261                               0.87                                        260                               2.0                                         258                               4.3                                         259                               2.2                                         256                               8.3                                         257                               9.0                                         246                               1.7                                         247                               1.2                                         254                               3.0                                         255                               1.6                                         248                               4.7                                         249                               0.75                                        251        0.123      70.84                                                              0.370      90.56                                                              1.100      97.68                                                              3.300      94.5                                                               10.000     94.16                                                              30.000     93.24                                                                                     1.9                                         253        0.123      94.03                                                              0.370      96.84                                                              1.100      97.64                                                              3.300      95.93                                                              10.000     96.95                                                              30.000     98.52                                                   252        0.123      69.96                                                              0.370      85.05                                                              1.100      89.69                                                              3.300      100.57                                                             10.000     96.21                                                              30.000     91.38                                                                                     1.6                                         262        0.123      91.8                                                               0.370      96.6                                                               1.100      97.13                                                              3.300      95.4                                                               10.000     94.17                                                              30.000     89.18                                                   263        0.123      98.08                                                              0.370      98.99                                                              1.100      99.1                                                               3.300      98.08                                                              10.000     96.21                                                              30.000     88.19                                                   264        0.123      67.18                                                              0.370      75.01                                                              1.100      67.71                                                              3.300      57.62                                                              10.000     53.69                                                              30.000     64.58                                                                                     3.7                                         265        0.123      33.23                                                              0.370      56.33                                                              1.100      57.78                                                              3.300      63.69                                                              10.000     80.29                                                              30.000     85.64                                                                                     1.0                                         ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        EXAMPLE                         PROTEASE                                                                              FITC                                  NUMBER  ENZYME      DOSE        % INHIB.                                                                              KI (NM)                               ______________________________________                                        280     HIV-1       0.123       95.28                                                 HIV-1       0.370       94.98                                                 HIV-1       1.100       93.01                                                 HIV-1       3.300       86.69                                                 HIV-1       10.000      78.64                                                 HIV-1       30.000      76.85                                                 HIV1TANDEM                      0.100                                 293     HIV-1       0.123       53.45                                                 HIV-1       0.370       77.51                                                 HIV-1       1.100       94.18                                                 HIV-1       3.300       103.03                                                HIV-1       10.000      97.41                                                 HIV-1       30.000      92.01   4.300                                 295     HIV1TANDEM                      0.071                                 281     HIV1TANDEM                      0.002                                         HIV1TANDEM                      0.004                                 285     HIV1TANDEM                      0.015                                         HIV-1       0.123       81.8                                                  HIV-1       0.370       95.8                                                  HIV-1       1.100       99.11                                                 HIV-1       3.300       109.33                                                HIV-1       10.000      104.61                                                HIV-1       30.000      86.84                                         286     HIV1TANDEM                      13.300                                        HIV-1       0.123       34.76                                                 HIV-1       0.370       68.74                                                 HIV-1       1.100       89.29                                                 HIV-1       3.300       93.11                                                 HIV-1       10.000      108.17                                                HIV-1       30.000      95.31                                         287     HIV1TANDEM                      0.038                                 283     HIV1TANDEM                      0.004                                 296     HIV1TANDEM                      0.042                                 291     HIV1TANDEM                      0.012                                         HIV1TANDEM                      0.026                                 289     HIV1TANDEM                      0.133                                 290     HIV1TANDEM                      1.880                                 298     HIV1TANDEM                      0.004                                         HIV1TANDEM                      0.003                                         HIV1TANDEM                      0.007                                 266     HIV1TANDEM                      0.033                                 272     HIV1TANDEM                      3.600                                 270     HIV1TANDEM                      0.024                                         HIV-1       0.123       75.26                                                 HIV-1       0.370       85.62                                                 HIV-1       1.100       93.45                                                 HIV-1       3.300       96.62                                                 HIV-1       10.000      94.57                                                 HIV-1       30.000      82.67                                         273     HIV1TANDEM                      2.300                                         HIV-1       0.123   <   10                                                    HIV-1       0.370       23.24                                                 HIV-1       1.100       75.38                                                 HIV-1       3.300       94.63                                                 HIV-1       10.000      95.93                                                 HIV-1       30.000      91                                            276     HIV1TANDEM                      33.000                                        HIV-1       0.123       16.49                                                 HIV-1       0.370       38.95                                                 HIV-1       1.100       66.1                                                  HIV-1       3.300       90.01                                                 HIV-1       10.000      90.97                                                 HIV-1       30.000      87.6                                          278     HIV1TANDEM                      0.040                                         HIV-1       0.123       76.76                                                 HIV-1       0.370       86.99                                                 HIV-1       1.100       95.6                                                  HIV-1       3.300       96.91                                                 HIV-1       10.000      93.32                                                 HIV-1       30.000      86.18                                         268     HIV1TANDEM                      0.835                                 271     HIV1TANDEM                      0.051                                 299     HIV-1       0.123       83.51                                                 HIV-1       0.370       104.76                                                HIV-1       1.100       117.95                                                HIV-1       3.300       115.61                                                HIV-1       10.000      128.03                                                HIV-1       30.000      102.89                                                HIV1TANDEM                      0.200                                 300     HIVTANDEM                       0.100                                         HIVTANDEM                       0.100                                         HIV-1       0.123       90.61                                                 HIV-1       0.370       99.05                                                 HIV-1       1.100       111.45                                                HIV-1       3.300       109.19                                                HIV-1       10.000      105.56                                                HIV-1       30.000      104.91                                        302     HIVTANDEM                       1.870                                         HIVTANDEM                       3.600                                         HIV-1       0.123       38                                                    HIV-1       0.370       65.57                                                 HIV-1       1.100       89.51                                                 HIV-1       3.300       118.39                                                HIV-1       10.000      104.49                                                HIV-1       30.000      92.16                                         304     HIV-1       0.123       92.01                                                 HIV-1       0.370       93.28                                                 HIV-1       1.100       96.47                                                 HIV-1       3.300       100.47                                                HIV-1       10.000      107.61                                                HIV-1       30.000      79.68                                                 HIV1TANDEM                      0.100                                         HIV1TANDEM                      0.050                                 305     HIV-1       0.123       99.99                                                 HIV-1       0.370       110.76                                                HIV-1       1.100       114.35                                                HIV-1       3.300       110.88                                                HIV-1       10.000      102.01                                                HIV-1       30.000      57.83                                                 HIV1TANDEM                      0.400                                 306     HIV-1       0.123       71.79                                                 HIV-1       0.370       82.71                                                 HIV-1       1.100       89.3                                                  HIV-1       3.300       97.29                                                 HIV-1       10.000      82.59                                                 HIV-1       30.000      53.43                                                 HIV1TANDEM                      0.040                                 307     HIV-1       0.123       77.39                                                 HIV-1       0.370       99.85                                                 HIV-1       1.100       107.87                                                HIV-1       3.300       93.34                                                 HIV-1       10.000      83.49                                                 HIV-1       30.000      69.74                                                 HIV1TANDEM                      0.072                                 308     HIV-1       0.123       75.06                                                 HIV-1       0.370       108.14                                                HIV-1       1.100       95.01                                                 HIV-1       3.300       108.43                                                HIV-1       10.000      110.75                                                HIV-1       30.000      96.28                                                 HIV1TANDEM                      0.074                                 310     HIV-1       0.123       16.81                                                 HIV-1       0.370       50.11                                                 HIV-1       1.100       78.69                                                 HIV-1       3.300       100.22                                                HIV-1       10.000      124.77                                                HIV-1       30.000      110.91                                                HIV1TANDEM                      1.500                                 311     HIV-1       0.123       86.51                                                 HIV-1       0.370       91.49                                                 HIV-1       1.100       101.8                                                 HIV-1       3.300       96.5                                                  HIV-1       10.000      93.77                                                 HIV-1       30.000      77.63                                                 HIV1TANDEM                      0.007                                 312     HIV1TANDEM                      0.255                                 314     HIV1TANDEM                      0.700                                         HIV-1       0.123       82.92                                                 HIV-1       0.370       96.14                                                 HIV-1       1.100       114.86                                                HIV-1       3.300       100.76                                                HIV-1       10.000      88.75                                                 HIV-1       30.000      73.42                                         315     HIV1TANDEM                      0.029                                         HIV-1       0.123       79.95                                                 HIV-1       0.370       87.25                                                 HIV-1       1.100       88.08                                                 HIV-1       3.300       97.03                                                 HIV-1       10.000      100.2                                                 HIV-1       30.000      106.4                                         316     HIV1TANDEM                      0.357                                         HIV-1       0.123       75.49                                                 HIV-1       0.370       85.02                                                 HIV-1       1.100       100.32                                                HIV-1       3.300       95.46                                                 HIV-1       10.000      99.71                                                 HIV-1       30.000      87.91                                         317     HIV1TANDEM                      0.040                                         HIV-1       0.123       87.38                                                 HIV-1       0.370       94.14                                                 HIV-1       1.100       98.45                                                 HIV-1       3.300       95.97                                                 HIV-1       10.000      101.26                                                HIV-1       30.000      108.59                                        318     HIV1TANDEM                      0.019                                         HIV-1       0.123       98.06                                                 HIV-1       0.370       106.35                                                HIV-1       1.100       101.88                                                HIV-1       3.300       88.73                                                 HIV-1       10.000      94.49                                                 HIV-1       30.000      82.83                                         319     HIV1TANDEM                      29.500                                        HIV-1       0.123       10.75                                                 HIV-1       0.370       32.65                                                 HIV-1       1.100       60.14                                                 HIV-1       3.300       75.86                                                 HIV-1       10.000      93.46                                                 HIV-1       30.000      74.48                                         320     HIV1TANDEM                      0.071                                         HIV1TANDEM                      0.050                                         HIV1TANDEM                      0.075                                 322     HIV1TANDEM                      1.070                                         HIV1TANDEM                      1.290                                 324     HIV1TANDEM                      0.156                                 326     HIV1TANDEM                      0.029                                 328     HIV-1                           22.000                                        HIV-1       0.123       27.81                                                 HIV-1       0.370       79.47                                                 HIV-1       1.100       95.45                                                 HIV-1       3.300       96.77                                                 HIV-1       10.000      96.78                                                 HIV-1       30.000      92.17                                         329     HIV-1                           12.000                                        HIV-1       0.123       46.4                                                  HIV-1       0.370       88.19                                                 HIV-1       1.100       96.63                                                 HIV-1       3.300       100.32                                                HIV-1       10.000      97.07                                                 HIV-1       30.000      96.35                                         330     HIV1TANDEM                      0.524                                         HIV-1       0.123       93.74                                                 HIV-1       0.370       94.32                                                 HIV-1       1.100       93.66                                                 HIV-1       3.300       85.63                                                 HIV-1       10.000      87.9                                                  HIV-1       30.000      69.82                                         331     HIV1TANDEM                      0.272                                         HIV-1       0.123       99.76                                                 HIV-1       0.370       104.06                                                HIV-1       1.100       108.51                                                HIV-1       3.300       99.3                                                  HIV-1       10.000      103.28                                                HIV-1       30.000      93.3                                          332     HIV1TANDEM                      0.400                                         HIV-1       0.123       81.87                                                 HIV-1       0.370       85.65                                                 HIV-1       1.100       86.23                                                 HIV-1       3.300       93.28                                                 HIV-1       10.000      91.68                                                 HIV-1       30.000      95.08                                                 HIV-1                           1.600                                 333     HIV-1       0.123       66.73                                                 HIV-1       0.370       85.07                                                 HIV-1       1.100       85.12                                                 HIV-1       3.300       93.69                                                 HIV-1       10.000      89.38                                                 HIV-1       30.000      77.91                                                 HIV-1                           7.700                                 334     HIV1TANDEM                      0.450                                         HIV-1       0.123       93.49                                                 HIV-1       0.370       90.25                                                 HIV-1       1.100       94.57                                                 HIV-1       3.300       102.47                                                HIV-1       10.000      97.61                                                 HIV-1       30.000      96.3                                          335     HIV-1       0.123       60.07                                                 HIV-1       0.370       99.75                                                 HIV-1       1.100       97.05                                                 HIV-1       3.300       92.06                                                 HIV-1       10.000      89.77                                                 HIV-1       30.000      76.25                                                 HIV1TANDEM                      0.040                                 336     HIV-1       0.123       65.64                                                 HIV-1       0.370       112                                                   HIV-1       1.100       89.54                                                 HIV-1       3.300       88.06                                                 HIV-1       10.000      77.12                                                 HIV-1       30.000      62.28                                                 HIV1TANDEM                      0.032                                 338     HIV-1       0.123       61.74                                                 HIV-1       0.370       85.32                                                 HIV-1       1.100       80.46                                                 HIV-1       3.300       89.62                                                 HIV-1       10.000      83.53                                                 HIV-1       30.000      62.34                                                 HIV1TANDEM                      0.100                                 339     HIV-1       0.123       83.49                                                 HIV-1       0.370       100.6                                                 HIV-1       1.100       101.42                                                HIV-1       3.300       104.71                                                HIV-1       10.000      91.38                                                 HIV-1       30.000      72.86                                                 HIV1TANDEM                      0.120                                 340     HIV-1       0.123       80.58                                                 HIV-1       0.370       90.49                                                 HIV-1       1.100       90.16                                                 HIV-1       3.300       91.57                                                 HIV-1       10.000      89.49                                                 HIV-1       30.000      71.99                                                 HIV1TANDEM                      0.060                                 342     HIV-1       0.123       81.06                                                 HIV-1       0.370       93.18                                                 HIV-1       1.100       96.94                                                 HIV-1       3.300       85.55                                                 HIV-1       10.000      73.55                                                 HIV-1       30.000      73.95                                                 HIV1TANDEM                      0.309                                 343     HIV-1       0.123       57.5                                                  HIV-1       0.370       76.83                                                 HIV-1       1.100       81.02                                                 HIV-1       3.300       86.43                                                 HIV-1       10.000      60.56                                                 HIV-1       30.000      46      2.900                                 344     HIV-1       0.123       47.37                                                 HIV-1       0.370       72.84                                                 HIV-1       1.100       81.17                                                 HIV-1       3.300       83.08                                                 HIV-1       10.000      68.47                                                 HIV-1       30.000      46.24   5.900                                 345     HIV1TANDEM                      0.032                                         HIV-1       0.123       69.19                                                 HIV-1       0.370       94.37                                                 HIV-1       1.100       101.67                                                HIV-1       3.300       99.08                                                 HIV-1       10.000      97.43                                                 HIV-1       30.000      84.56                                         347     HIV1TANDEM                      13.600                                        HIV-1       0.123       20.99                                                 HIV-1       0.370       50.82                                                 HIV-1       1.100       71.4                                                  HIV-1       3.300       83                                                    HIV-1       10.000      90.97                                                 HIV-1       30.000      87.18                                         348     HIV1TANDEM                      1.960                                         HIV-1       0.123       53.47                                                 HIV-1       0.370       78.32                                                 HIV-1       1.100       89.84                                                 HIV-1       3.300       92.96                                                 HIV-1       10.000      96.28                                                 HIV-1       30.000      84.67                                         349     HIV1TANDEM                      0.111                                         HIV-1       0.123       74.5                                                  HIV-1       0.370       88.21                                                 HIV-1       1.100       99.92                                                 HIV-1       3.300       104.99                                                HIV-1       10.000      103.49                                                HIV-1       30.000      98.24                                         351     HIV-1       0.123   <   10                                                    HIV-1       0.370   <   10                                                    HIV-1       1.100       25.4                                                  HIV-1       3.300       55.11                                                 HIV-1       10.000      78.53                                                 HIV-1       30.000      90.55                                                 HIV-1                           558.000                               352     HIV-1       0.123   <   10                                                    HIV-1       0.370       25.31                                                 HIV-1       1.100       47.78                                                 HIV-1       3.300       74.99                                                 HIV-1       10.000      85.86                                                 HIV-1       30.000      87.82                                                 HIV-1                           168.000                               353     HIV-1                           10.400                                        HIV1TANDEM                      5.300                                         HIV-1       0.123       51.83                                                 HIV-1       0.370       68.49                                                 HIV-1       1.100       70.71                                                 HIV-1       3.300       63.96                                                 HIV-1       10.000      51.8                                                  HIV-1       30.000      43.93                                         354     HIV-1       0.123   <   10                                                    HIV-1       0.370       10.37                                                 HIV-1       1.100       26.79                                                 HIV-1       3.300       46.1                                                  HIV-1       10.000      54.97                                                 HIV-1       30.000      54.5                                                  HIV-1                           665.000                               355     HIV-1                           700.000                                       HIV-1       0.123   <   10                                                    HIV-1       0.370   <   10                                                    HIV-1       1.100   <   10                                                    HIV-1       3.300       20.72                                                 HIV-1       10.000      46.66                                                 HIV-1       30.000      67.82                                         356     HIV1TANDEM                      1.100                                         HIV-1       0.123       54.96                                                 HIV-1       0.370       71.75                                                 HIV-1       1.100       90.19                                                 HIV-1       3.300       92.28                                                 HIV-1       10.000      100.22                                                HIV-1       30.000      95.16                                         357     HIV1TANDEM                      48.500                                359     HIV1TANDEM                      16.400                                363     HIV1TANDEM                      0.083                                 365     HIV1TANDEM                      0.023                                 368     HIV1TANDEM                      0.232                                 370     HIV-1       0.123       92.81                                                 HIV-1       0.370       87.87                                                 HIV-1       1.100       102.89                                                HIV-1       3.300       109.33                                                HIV-1       10.000      113.79                                                HIV-1       30.000      98.14   0.590                                         HIV1TANDEM                      0.050                                         HIV-2                           0.050                                 371     HIV-1       0.123       39.84                                                 HIV-1       0.370       72.94                                                 HIV-1       1.100       91.61                                                 HIV-1       3.300       104.12                                                HIV-1       10.000      102.7                                                 HIV-1       30.000      107.21  15.400                                372     HIV-1       0.123       43.52                                                 HIV-1       0.370       86.68                                                 HIV-1       1.100       101.52                                                HIV-1       3.300       99.56                                                 HIV-1       10.000      97.81                                                 HIV-1       30.000      106.18  4.000                                 373     HIV-1       0.123       90.71                                                 HIV-1       0.370       90.35                                                 HIV-1       1.100       103.83                                                HIV-1       3.300       88.72                                                 HIV-1       10.000      85.75                                                 HIV-1       30.000      89.53                                                 HIV1TANDEM                      0.200                                 374     HIV1TANDEM  0.123       78.97                                                             0.370       82.14                                                             1.100       84.98                                                             3.300       87.70                                                             10.000      95.25                                                             30.000      80.11   0.031                                 ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        U-No. MS data  Name               Origin                                      ______________________________________                                        300   587.2453 5-Cyano-N- 3(R or S)-(1- 5,6-                                                                    Single                                            (EI)     dihydro-4-hydroxy-2-oxo-6(R or                                                                   stereoisomer;                                              S)-(2-phenylethyl)-6-propyl-2H-                                                                  Derived from                                               pyran-3-yl!-2,2-dimethylpropyl)-                                                                 Isomer 1 of                                                phenyl!-2-pyridinesulfonamide                                                                    Preparation 143                             301   587.2458 5-Cyano-N- 3(R or S)-(1- 5,6-                                                                    Single                                            (EI)     dihydro-4-hydroxy-2-oxo-6(R or                                                                   stereoisomer;                                              S)-(2-phenylethyl)-6-propyl-2H-                                                                  Derived from                                               pyran-3-yl!-2,2-dimethylpropyl)-                                                                 Isomer 2 of                                                phenyl!-2-pyridinesulfonamide                                                                    Preparation 143                             302   587.2444 5-Cyano-N- 3(R or S)-(1- 5,6-                                                                    Single                                            (EI)     dihydro-4-hydroxy-2-oxo-6(R or                                                                   stereoisomer;                                              S)-(2-phenylethyl)-6-propyl-2H-                                                                  Derived from                                               pyran-3-yl!-2,2-dimethylpropyl)-                                                                 Isomer 3 of                                                phenyl!-2-pyridinesulfonamide                                                                    Preparation 143                             303   587.2446 5-Cyano-N- 3(R or S)-(1- 5,6-                                                                    Single                                            (EI)     dihydro-4-hydroxy-2-oxo-6(R or                                                                   stereoisomer;                                              S)-(2-phenylethyl)-6-propyl-2H-                                                                  Derived from                                               pyran-3-yl!-2,2-dimethylpropyl)-                                                                 Isomer 4 of                                                phenyl)-2-pyridinesulfonamide                                                                    Preparation 143                             304   525.2311 5-Cyano-N- 3-(1- 5,6-dihydro-6,6-                                                                Racemic                                           (EI)     diisobutyl-4-hydroxy-2-oxo-2H-                                                                   mixture                                                    pyran-3-yl!propyl)phenyl!-2-                                                  pyridinesulfonamide                                            305   532.2856 N- 3-(1- 5,6-Dihydro-6,6-                                                                        Racemic                                           (FAB)    diisobutyl-4-hydroxy-2-oxo-2H-                                                                   mixture                                                    pyran-3-yl!-2,2-dimethylpropyl)-                                              phenyl!-1-methyl-1H-imidazole-4-                                              sulfonamide                                                    306   554.2688 5-Cyano-N- 3-(1- 5,6-dihydro-6,                                                                  Racemic                                           (FAB)    6-diisobutyl-4-hydroxy-2-oxo-2H-                                                                 mixture                                                    pyran-3-yl!-2,2-dimethylpropyl)-                                              phenyl!-2-pyridinesulfonamide                                  307   565.2607 N- 3(R or S)- 1-(5,6-Dihydro-4-                                                                  Single                                            (EI)     hydroxy-2-oxo-6(R or S)- 2-                                                                      stereoisomer;                                              phenylethyl!-6-propyl-2H-pyran-3-                                                                Derived from                                               yl)-2,2-dimethylpropyl!phenyl!-1-                                                                Isomer 1 of                                                methyl-1H-imidazole-4-                                                                           Preparation 143                                            sulfonamide                                                    308   565.2629 N- 3(R or S)- 1-(5,6-Dihydro-4-                                                                  Single                                            (EI)     hydroxy-2-oxo-6(R or S)- 2-                                                                      stereoisomer;                                              phenylethyl!-6-propyl-2H-pyran-3-                                                                Derived from                                               yl)-2,2-dimethylpropyl!phenyl!-1-                                                                Isomer 2 of                                                methyl-1H-imidazole-4-                                                                           Preparation 143                                            sulfonamide                                                    309   565.2605 N- 3(R or S)- 1-(5,6-Dihydro-4-                                                                  Single                                            (EI)     hydroxy-2-oxo-6(R or S)- 2-                                                                      stereoisomer;                                              phenylethyl!-6-propyl-2H-pyran-3-                                                                Derived from                                               yl)-2,2-dimethylpropyl!phenyl!-1-                                                                Isomer 3 of                                                methyl-1H-imidazole-4-                                                                           Preparation 143                                            sulfonamide                                                    310   565.2626 N- 3(R or S)- 1-(5,6-Dihydro-4-                                                                  Single                                            (EI)     hydroxy-2-oxo-6(R or S)- 2-                                                                      stereoisomer;                                              phenylethyl!-6-propyl-2H-pyran-3-                                                                Derived from                                               yl)-2,2-dimethylpropyl!phenyl!-1-                                                                Isomer 4 of                                                methyl-1H-imidazole-4-                                                                           Preparation 148                                            sulfonamide                                                    311   571.2113 5-Cyano-N- 3-(1- 5,6-dihydro-4-                                                                  Diastereomeric                                    (EI)     hydroxy-2-oxo-6-(2-phenylethyl)-                                                                 mixture                                                    6-propyl-2H-pyran-3-yl!cycloprop-                                             yl-methyl)phenyl!-2-pyridine-                                                 sulfonamide                                                    312   577.2630 5-Amino-N- 3(R or S)-(1- 5,6-                                                                    Single                                            (EI)     dihydro-4-hydroxy-2-oxo-6(R or                                                                   stereoisomer;                                              S)-(2-phenylethyl)-6-propyl-2H-                                                                  Prepared from                                              pyran-3-yl!-2,2-dimethylpropyl)-                                                                 amine of                                                   phenyl!-2-pyridinesulfonamide                                                                    Preparation 138                                                               (derived from                                                                 Isomer 1 of                                                                   Preparation                                                                   143)                                        313   577.2585 5-Amino-N- 3(R or S)-(1- 5,6-                                                                    Single                                            (EI)     dihydro-4-hydroxy-2-oxo-6(R or                                                                   stereoisomer;                                              S)-(2-phenylethyl)-6-propyl-2H-                                                                  Prepared from                                              pyran-3-yl!-2,2-dimethylpropyl)-                                                                 amine of                                                   phenyl!-2-pyridinesulfonamide                                                                    Preparation 137                                                               (derived from                                                                 Isomer 2 of                                                                   Preparation                                                                   143)                                        314   550.2380 5-Amino-N- 3(R or S)-(1- 5,6-                                                                    Single                                            (FAB)    dihydro-4-hydroxy-2-oxo-6(R or                                                                   stereoisomer;                                              S)-(2-phenylethyl)-6-propyl-2H-                                                                  Derived from                                               pyran-3-yl!propyl)phenyl!-2-                                                                     Isomer 1 of                                                pyridinesulfonamide                                                                              Preparation 147                             315   550.2365 5-Amino-N- 3(R or S)-(1- 5,6-                                                                    Single                                            (FAB)    dihydro-4-hydroxy-2-oxo-6(R or                                                                   stereoisomer;                                              S)-(2-phenylethyl)-6-propyl-2H-                                                                  Derived from                                               pyran-3-yl!propyl)phenyl!-2-                                                                     Isomer 2 of                                                pyridinesulfonamide                                                                              Preparation 147                             316   596.2583 5-Amino-N- 3(R or S)-(1- 6(R or                                                                  Single                                            (FAB)    S)-(2- 4-fluorophenyl)ethyl)-5,6-                                                                stereoisomer;                                              dihydro-4-hydroxy-2-oxo-6-propyl-                                                                Derived from                                               2H-pyran-3-yl!-2,2-dimethyl                                                                      Isomer 1 of                                                propyl)phenyl!-2-pyridine-                                                                       Preparation 150                                            sulfonamide                                                    317   596.2583 5-Amino-N- 3(R or S)-(1- 6(R or                                                                  Single                                            (FAB)    S)-(2- 4-fluorophenyl!ethyl)-5,6-                                                                stereoisomer;                                              dihydro-4-hydroxy-2-oxo-6-propyl-                                                                Derived from                                               2H-pyran-3-yl!-2,2-dimethyl-                                                                     Isomer 2 of                                                propyl)phenyl!-2-pyridine-                                                                       Preparation 150                                            sulfonamide                                                    318   503.2445 N- 3(R or S)-(1- 5,6-Dihydro-6,6-                                                                Single                                            (EI)     dipropyl-4-hydroxy-2-oxo-2H-                                                                     enantiomer;                                                pyran-3-yl!-2,2-dimethylpropyl)-                                                                 Prepared from                                              phenyl!-1-methyl-1H-imidazole-4-                                                                 amine derived                                              sulfonamide        from Isomer 1                                                                 of Preparation                                                                144                                         319   503.2454 N- 3(R or S)-(1- 5,6-Dihydro-6,6-                                                                Single                                            (EI)     dipropyl-4-hydroxy-2-oxo-2H-                                                                     enantiomer;                                                pyran-3-yl!-2,2-dimethylpropyl)-                                                                 Prepared from                                              phenyl!-1-methyl-1H-imidazole-4-                                                                 amine derived                                              sulfonamide        from Isomer 2                                                                 of Preparation                                                                144                                         320   515.2453 5-Amino-N- 3(R or S)-(1- 5,6-                                                                    Single                                            (EI)     dihydro-6,6-dipropyl-4-hydroxy-2-                                                                enantiomer;                                                oxo-2H-pyran-3-yl!-2,2-dimethy-                                                                  Prepared from                                              lpropyl)phenyl!-2-pyridine-                                                                      amine derived                                              sulfonamide        from Isomer 1                                                                 of Preparation                                                                144                                         321   515.2463 5-Amino-N- 3(R or S)-(1- 5,6-                                                                    Single                                            (EI)     dihydro-6,6-dipropyl-4-hydroxy-2-                                                                enantiomer;                                                oxo-2H-pyran-3-yl!-2,2-dimethyl-                                                                 Prepared from                                              propyl)phenyl!-2-pyridine-                                                                       amine derived                                              sulfonamide        from Isomer 2                                                                 of Preparation                                                                144                                         322   525.2287 5-Cyano-N- 3(R or S)-(1- 5,6-                                                                    Single                                            (EI)     dihydro-6,6-dipropyl-4-hydroxy-2-                                                                enantiomer;                                                oxo-2H-pyran-3-yl!-2,2-dimethyl-                                                                 Prepared from                                              propyl)phenyl!-2-pyridine-                                                                       amine derived                                              sulfonamide        from Isomer 2                                                                 of Preparation                                                                144                                         323   525.2288 5-Cyano-N- 3(R or S)-(1- 5,6-                                                                    Single                                            (EI)     dihydro-6,6-dipropyl-4-hydroxy-2-                                                                enantiomer;                                                oxo-2H-pyran-3-yl!-2,2-dimethyl-                                                                 Prepared from                                              propyl)phenyl!-2-pyridine-                                                                       amine derived                                              sulfonamide        from Isomer 1                                                                 of Preparation                                                                144                                         324   600.2537 N- 3(R or S)-(1- 6,6-Bis(2-phenyl-                                                               Single                                            (FAB)    ethyl)-5,6-dihydro-4-hydroxy-2-                                                                  enantiomer;                                                oxo-2H-pyran-3-yl!propyl)phenyl!-                                                                Prepared from                                              1-methyl-1H-imidazole-4-                                                                         amine derived                                              sulfonamide        from Isomer 1                                                                 of Preparation                                                                145                                         325   600.2537 N- 3(R or S)-(1- 6,6-Bis(2-phenyl-                                                               Single                                            (FAB)    ethyl)-5,6-dihydro-4-hydroxy-2-                                                                  enantiomer;                                                oxo-2H-pyran-3-yl!propyl)phenyl!-                                                                Prepared from                                              1-methyl-1H-imidazole-4-                                                                         amine derived                                              sulfonamide        from Isomer 2                                                                 of Preparation                                                                145                                         326   622.2378 N- 3(R or S)-(1- 6,6-Bis(2-phenyl-                                                               Single                                            (FAB)    ethyl)-5,6-dihydro-4-hydroxy-2-                                                                  enantiomer;                                                oxo-2H-pyran-3-yl!propyl)phenyl!-                                                                Prepared from                                              5-cyano-2-pyridinesulfonamide                                                                    amine derived                                                                 Isomer 1 of                                                                   Preparation 145                             327   622.2367 N- 3(R or S)-(1- 6,6-Bis(2-phenyl-                                                               Single                                            (FAB)    ethyl)-5,6-dihydro-4-hydroxy-2-                                                                  enantiomer;                                                oxo-2H-pyran-3-yl!propyl)phenyl!-                                                                Prepared from                                              5-cyano-2-pyridinesulfonamide                                                                    amine derived                                                                 from Isomer 2                                                                 of Preparation                                                                145                                         ______________________________________                                    

We claim:
 1. The compound of the formula VI ##STR3## wherein R₂ is a) H₃C--CH₂ --, orb) phenyl-(CH₂)₂ --; wherein R₃ is the moiety of formula X##STR4## wherein R₆ is a) H₃ C--(CH₂)₂ --, orb) phenyl-(CH₂)₂ --;wherein R₇ is H₃ C--CH₂ --; wherein R₉ is --NHSO₂ --het; wherein het is2-pyridinyl substituted at the 5-position by zero (0) or one (1) R₁₀ ;wherein R₁₀ isa) --CN, b) --CF₃, c) --NH2, or d) --CONH₂ ;or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1selected from the group consisting of: ##STR5##
 3. The compound of claim1 selected from the group consisting of:5-Trifluoromethyl-N- 3-(R or S)-1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide;5-Trifluoromethyl-N- 3-(R)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide;or (3R)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide;5-Trifluoromethyl-N- 3-(S)- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide;or (3S)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide;5-Trifluoromethyl-N- 3(R or S)- 1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenethyl)-6(R orS)-n-propyl-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridine sulfonamide;5-Trifluoromethyl-N- 3(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6(R)-n-propyl-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide;or (3R,6R)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl)propyl!-phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide;5-Trifluoromethyl-N- 3(R)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)-n-propyl-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide;or (3R,6S)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl)propyl!-phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide;5-Trifluoromethyl-N- 3(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6(R)-n-propyl-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide;or (3S,6R)-N- 3- 1-5,6,-Dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide;5-Trifluoromethyl-N- 3(S)- 1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)-n-propyl-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide;or (3S,6S)-N- 3- 1-5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide;N- 3- 1-(S)-5,6,-Dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide;(3R)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide;N- 3-{1(R orS)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-propyl}phenyl!-5-cyanopyridine-2-sulfonamide;N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-propyl}phenyl!-5-cyanopyridine-2-sulfonamide;N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-propyl}phenyl!-5-cyanopyridine-2-sulfonamide;N- 3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R orS)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide;N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide;N-3-{1(R)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide;N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(R)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide;N-3-{1(S)-(4-Hydroxy-5,6-dihydro-2-oxo-6(S)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide;5-Amino-N- 3(R or S)-(1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl)phenyl!-2-pyridinesulfonamide;5-Amino-N- 3(R or S)-(1- 5,6-dihydro-4-hydroxy-2-oxo-6(R orS)-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl)phenyl!-2-pyridinesulfonamide;5-Trifluoromethyl-N- 3- 1-4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide;N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide;N- 3(R or S)-(1-6,6-Bis(2-phenylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!propyl)phenyl!-5-cyano-2-pyridinesulfonamide;N- 3(R or S)-(1-6,6-Bis(2-phenyl-ethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl!propyl)phenyl!-5-cyano-2-pyridinesulfonamide;N- 3-{1(R orS)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-propyl}phenyl!-5-aminopyridine-2-sulfonamide;N- 3-{1(S orR)-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)-propyl}phenyl!-5-aminopyridine-2-sulfonamide;5-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide;5-Trifluoromethyl-N- 3-(R or S)- 1-4-hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H-pyran-3-yl!-propyl!-phenyl!-2-pyridinesulfonamide;N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide;N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl}phenyl!-5-cyanopyridine-2-sulfonamide;and N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-pyran-3-yl)propyl}phenyl!-5-carbamoylpyridine-2-sulfonamide.4. The compound of claim 1 selected from the group consistingof:(3R,6R)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide;(3R,6S)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide;(3S,6R)-N- 3- 1-5,6,-Dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide;(3S,6S)-N- 3- 1-5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide;N- 3- 1-(S)-5,6,-Dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl!propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide;and (3R)-N- 3-1-(5,6-Dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-pyran-3-yl)propyl!phenyl!-5-(trifluoromethyl)-2-pyridinesulfonamide.5. A compound selected from the group consisting of:N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)methyl}phenyl!-5-cyanopyridine-2-sulfonamide,and N-3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-pyran-3-yl)methyl}phenyl!-5-aminopyridine-2-sulfonamide.